Rebound-associated vertebral fractures after discontinuation of denosumab for the treatment of maxillitis.

We reported a 69-year-old female who discontinued denosumab due to dental treatment and subsequently suffered rebound-associated vertebral fractures 10 months after the last injection. This case raised an alarm regarding the discontinuation of denosumab for dental treatment. Denosumab, a human monoclonal antibody administered by subcutaneous injection, to the best of our knowledge, is the only fully investigated inhibitor of receptor activator of nuclear factor kappa B ligand. Discontinuation of denosumab leads to bone turnover rebound and rapid bone mineral density loss. Several studies have reported rebound-associated vertebral fractures after discontinuation of denosumab. We report on a new case of rebound-associated vertebral fractures after discontinuation of denosumab. A 69-year-old female, who withdrew from denosumab treatment after 3 years due to maxillitis, presented to our hospital with severe low back pain without any history of trauma. Ten months had passed since the last injection. Magnetic resonance imaging showed five acute vertebral fractures, which appeared to be rebound-associated vertebral fractures caused by discontinuation of denosumab due to dental treatment. This case clearly demonstrates the risk of discontinuation of denosumab for dental treatment.

A retrospective analysis of nonresponse to daily teriparatide treatment.

UNLABELLED: Some patients with osteoporosis do not respond to teriparatide treatment. Prior bisphosphonate use, lower bone turnover marker (BTMs) concentrations, and lower early increases in BTMs were significantly associated with a blunted lumbar spine (LS) bone mineral density (BMD) response to daily treatment with teriparatide, although the impact was limited. INTRODUCTION: Some osteoporosis patients do not respond to teriparatide treatment. To better understand the factors underlying treatment nonresponses, we compared nonresponders' and responders' characteristics. METHODS: We retrospectively analyzed 354 male and female patients with osteoporosis who were administered teriparatide (20 µg/day) for 24 months. The patients were categorized as responders (≥3 % lumber spine (LS) bone mineral density (BMD) increase) or nonresponders (<3 % LS BMD increase), and the groups were compared. RESULTS: The univariate analyses determined that prior bisphosphonate use, a lower baseline procollagen type I N-terminal propeptide (PINP) concentration and a lower urinary N-telopeptide of type I collagen (uNTX) concentration at baseline were significantly associated with teriparatide nonresponses, but these factors were not significant following multivariate analysis. Diminished early increases in the bone turnover markers (BTMs) were also related to nonresponses after teriparatide treatment began. In the nonresponders, the mean (standard deviation (SD)) absolute LS and femoral neck (FN) BMD changes were -0.002 g/cm(2) (0.032) and -0.010 g/cm(2) (0.045), respectively. In the responders, the mean (SD) absolute LS and FN BMD changes were 0.118 g/cm(2) (0.056) and 0.021 g/cm(2) (0.046), respectively. The serum PINP and uNTX levels increased rapidly in both groups, but the responders showed higher early absolute serum PINP and uNTX increases. CONCLUSIONS: The factors associated with nonresponses were prior bisphosphonate use, lower baseline BTM levels, and lower early increases in the BTMs after starting teriparatide treatment, but the impact of these factors on achieving a ≥3 % LS BMD increase at 24 months was limited.

Usefulness of daily teriparatide treatment in elderly patients over 80 years of age.

UNLABELLED: The percent and absolute lumbar spine and femoral neck bone mineral densities and procollagen type I N-terminal propeptide (PINP) and urinary N-telopeptide level increases noted after teriparatide 20 µg/day treatment for 24 months were similar in the older (age ≥ 80 years) and younger (age < 80 years) subgroups. INTRODUCTION: Many individuals are living into their eighth and ninth decades, but little is known about the efficacy of osteoporosis medication for this population. We retrospectively compared usefulness of daily teriparatide therapy in osteoporosis patients ≥80 and <80 years to detect possible age-related differences. METHODS: We analyzed 628 osteoporosis patients treated with teriparatide 20 µg/day for 24 months. The primary efficacy measures were changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) over 24 months. Changes in serum procollagen type I N-terminal propeptide levels and urinary N-telopeptide (uNTX) excretion were also measured. Patients were divided into age subgroups (older, ≥80 years; younger, <80 years) for BMD and bone turnover marker comparison. RESULTS: In the older subgroup, the percent LS BMD significantly increased by 14.6 ± 10.4 % (mean ± SD) and FN BMD significantly increased by 4.5 ± 10.7 % at 24 months. In the younger subgroup, the percent LS BMD significantly increased by 12.2 ± 8.5 % and FN BMD significantly increased by 2.9 ± 8.3 % at 24 months. In the older subgroup, the mean absolute LS BMD change was 0.111 ± 0.071 g/cm(2) and FN BMD change was 0.019 ± 0.043 g/cm(2). In the younger subgroup, the mean absolute LS BMD change was 0.098 ± 0.065 g/cm(2) and FN BMD change was 0.016 ± 0.045 g/cm(2). The percent and absolute BMD increases in LS and FN and changes in PINP and uNTX were similar between the subgroups. CONCLUSIONS: The usefulness of daily teriparatide treatment is not age dependent.

Analysis of daily teriparatide treatment for osteoporosis in men.

UNLABELLED: The percent and absolute lumbar spine and femoral neck bone mineral densities and absolute procollagen type I N-terminal propeptide (PINP) increases following a 20-µg/day teriparatide treatment for 12 months were similar in men and women regardless of sex differences. INTRODUCTION: Several placebo-controlled studies have measured the effects of daily teriparatide in men and postmenopausal women with osteoporosis but none have directly compared the effects between these groups. We retrospectively compared the effects of daily teriparatide therapy in men and postmenopausal women with osteoporosis and investigated biochemical markers of bone turnover to detect possible sex differences. METHODS: Patients (563; 75 men and 488 women) with osteoporosis were retrospectively investigated. All patients were administered with teriparatide at 20 µg/day for 12 months. The primary efficacy measure was changed in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD) after 12 months of treatment. The change in serum levels of procollagen type I N-terminal propeptide (PINP) and urinary N-telopeptide (uNTX) excretion after 4, 8 and 12 months of treatment were also measured. RESULTS: In men, the percent LS BMD significantly increased by 11.3 ± 9.9 % (mean ± standard deviation (SD)) and the FN BMD increased by 0.4 ± 6.4 % without a significant difference at 12 months. In postmenopausal women, the percent LS BMD significantly increased by 9.6 ± 8.1 % and the FN BMD significantly increased by 2.4 ± 7.8 % at 12 months. The percent and absolute BMD increases in LS and FN between men and women were similar. The absolute increases in PINP were similar in both groups at 4, 8 and 12 months. However, the absolute increases in uNTX were significantly lower in men than in women at 8 and 12 months. CONCLUSION: Daily teriparatide treatment was as effective in men as in postmenopausal women regardless of sex differences.

An algorithm using the early changes in PINP to predict the future BMD response for patients treated with daily teriparatide.

UNLABELLED: About two thirds of patients with a procollagen type I N-terminal propeptide (PINP) increase of >80 µg/l at 1 month after starting teriparatide therapy showed a ≥10 % increase in lumbar spine (LS) bone mineral density (BMD) from baseline at 12 months. We recommend this algorithm as an aid in the clinical management of patients treated with daily teriparatide. INTRODUCTION: An algorithm using PINP is provided in osteoporotic patients with teriparatide treatment. The correlations between the early changes in PINP and the subsequent BMD changes after daily teriparatide therapy were studied to develop an algorithm to monitor patients. METHODS: We evaluated whether early changes in PINP correlated with the changes in BMD at 12 months and developed an algorithm using the early changes in PINP to predict the upcoming BMD increases. RESULTS: The highest correlation coefficient for the relationship between PINP and LS BMD response was determined for the absolute change in PINP at 1 month and the percent change in LS BMD at 12 months (r = 0.36, p <0.01). Using a receiver operator curve analysis, we determined that an 80 µg/l increase in PINP was the most convenient predictor of a 10% increase in LS BMD from baseline (area under curve = 0.72). Using a cut-off value of 80 µg/l, the positive predictive value for predicting a 10% increase in LS BMD from baseline to 12 months was 65%. CONCLUSION: Greater short-term changes in PINP with teriparatide therapy are associated with greater 12-month increases in LS BMD. About two thirds of patients with a PINP increase of >80 µg/l at 1 month after starting treatment showed a ≥10 % increase in LS BMD from baseline at 12 months. We recommend this algorithm as an aid in the clinical management of patients treated with teriparatide.

Efficacy of the dynamic radiographs for diagnosing acute osteoporotic vertebral fractures.

UNLABELLED: We investigated the efficacy of dynamic radiographs for diagnosing acute osteoporotic vertebral fractures (OVFs) compared with supine radiographs or sitting radiographs alone. Evaluation of the dynamic radiographs was superior to the other evaluations. Dynamic radiographs provide a convenient and useful method of diagnosing acute OVFs. INTRODUCTION: Identifying acute OVFs on plain radiographs is difficult. We studied a new approach to identify acute OVFs on the basis of fracture mobility. METHODS: We performed a retrospective radiographic analysis of 472 acute OVFs (<3 weeks after onset), which were diagnosed on the basis of magnetic resonance imaging of T5 through L5 (a total of 5,239 vertebrae). Supine lateral radiographs were compared with sitting lateral radiographs to determine the presence or absence of mobility. Vertebrae showing changes in the vertebral body height were diagnosed as acute OVFs. We analyzed the diagnostic accuracy on the basis of comparative supine and sitting lateral radiographs and compared it with that of radiographs obtained in the supine or the sitting position alone. RESULTS: Of the 472 acute OVFs diagnosed, 313 (66 %) exhibited vertebral mobility on supine lateral and sitting lateral radiographs. Correct diagnoses of acute OVFs or no acute OVFs were made in 4,883 vertebrae. There were 159 unreadable OVFs (3 %), and 197 previous OVFs (4 %) were misdiagnosed as acute OVFs. The sensitivity was 66 % and the specificity was 96 %. Evaluation of the mobility of acute OVFs in the supine and the sitting position was superior to evaluation using radiographs in either the supine or the sitting position alone. CONCLUSIONS: Dynamic radiographs provide a convenient way to identify acute OVFs.

Automatic screening of narrow anterior chamber angle and angle-closure glaucoma based on slit-lamp image analysis by using support vector machine.

At present, Van Herick's method is a standard technique used to screen a Narrow Anterior Chamber Angle (NACA) and Angle-Closure Glaucoma (ACG). It can identify a patient who suffers from NACA and ACG by considering the width of peripheral anterior chamber depth (PACD) and corneal thickness. However, the screening result of this method often varies among ophthalmologists. So, an automatic screening of NACA and ACG based on slit-lamp image analysis by using Support Vector Machine (SVM) is proposed. SVM can automatically generate the classification model, which is used to classify the result as an angle-closure likely or an angle-closure unlikely. It shows that it can improve the accuracy of the screening result. To develop the classification model, the width of PACD and corneal thickness from many positions are measured and selected to be features. A statistic analysis is also used in the PACD and corneal thickness estimation in order to reduce the error from reflection on the cornea. In this study, it is found that the generated models are evaluated by using 5-fold cross validation and give a better result than the result classified by Van Herick's method.

Two cases of acute myositis associated with influenza A virus infection in the elderly.

During the influenza epidemic of 1998-1999, we observed two elderly patients with influenza-like symptoms who had evidence of acute myositis with elevated serum enzymes. Influenza A infection was confirmed serologically in either case. The present cases suggest that it is important to distinguish influenzal myositis from other forms of myopathy in the elderly patients.

E1A inhibits transforming growth factor-beta signaling through binding to Smad proteins.

Smads form a recently identified family of proteins that mediate intracellular signaling of the transforming growth factor (TGF)-beta superfamily. Smads bind to DNA and act as transcriptional regulators. Smads interact with a variety of transcription factors, and the interaction is likely to determine the target specificity of gene induction. Smads also associate with transcriptional coactivators such as p300 and CBP. E1A, an adenoviral oncoprotein, inhibits TGF-beta-induced transactivation, and the ability of E1A to bind p300/CBP is required for the inhibition. Here we determined the Smad interaction domain (SID) in p300 and found that two adjacent regions are required for the interaction. One of the regions is the C/H3 domain conserved between p300 and CBP, and the other is a nonconserved region. p300 mutants containing SID inhibit transactivation by TGF-beta in a dose-dependent manner. E1A inhibits the interaction of Smad3 with a p300 mutant that contains SID but lacks the E1A binding domain. We found that E1A interacts specifically with receptor-regulated Smads, suggesting a novel mechanism whereby E1A antagonizes TGF-beta signaling.

Intracellular signaling of the TGF-beta superfamily by Smad proteins.

TGF-beta is a potent inhibitor of cell growth, and accumulating evidence suggests that perturbation of the TGF-beta signaling pathway leads to tumorigenesis. Smads are recently identified proteins that mediate intracellular signaling of the TGF-beta superfamily. Smads 2 and 3 are phosphorylated by the TGF-beta type I receptor. Smad4 was originally identified as a candidate tumor suppressor gene in pancreatic cancers. Smads 2 and 3 form complexes with Smad4 upon TGF-beta stimulation. The heteromeric Smad complexes translocate into the nucleus, where they activate expression of target genes. Our recent study demonstrated that Smads exist as monomers in the absence of TGF-beta. Smads 2 and 3 form homo- as well as hetero-oligomers with Smad4 upon ligand stimulation. Both homo-oligomers and hetero-oligomers directly bind to DNA, suggesting that the signaling pathway of Smads may be multiplex. Smads 2 and 3 associate with transcriptional coactivators such as p300 in a ligand-dependent manner, p300 enhances transactivation by TGF-beta, suggesting that coactivators link Smads to the basal transcriptional machinery. A missense mutation of Smad2 identified in colorectal and lung cancers was introduced to Smad3. The mutant, Smad3(DE), blocked the activation of wild-type Smad2 and Smad3. Thus, the missense mutation not only disrupts the function of the wild-type Smad but also creates a dominant-negative Smad, which could actively contribute to oncogenesis.

Role of p300, a transcriptional coactivator, in signalling of TGF-beta.

BACKGROUND: Smad proteins are novel transcriptional regulators mediating the signalling of the transforming growth factor-beta (TGF-beta) superfamily. Coactivators such as p300/CBP promote transactivation by various transcription factors through a direct interaction with them. Adenoviral oncoprotein E1A, which binds p300, was shown to inhibit the signalling of TGF-beta. These findings raise the possibility that p300 may be involved in TGF-beta signalling. RESULTS: We investigated whether p300 is involved in transactivation by Smads. p300 enhanced the Smad-induced transactivation of p3TP-Lux, a TGF-beta responsive reporter. E1A inhibited this enhancement, and the inhibition required its ability to bind p300/CBP. p300 and Smad3, as well as Smad2, interacted in vivo in a ligand-dependent manner. The binding region in Smad3 was its C-terminal half that was previously shown to possess an intrinsic transactivation activity. The binding region in p300 was mapped to its C-terminal 678 amino acids. The minimal Smad2/3-interacting region, as well as the rest of the p300, inhibited the transactivation of p3TP-Lux in a dominant-negative fashion. CONCLUSION: p300 interacted with Smad2 and Smad3 in a ligand-dependent manner, and enhanced the transactivation by Smads. Our results present the molecular basis of the transactivation by Smad proteins.

Effects of lysophosphatidic acid on proliferation of stellate cells and hepatocytes in culture.

Lysophosphatidic acid (LPA) is a growth factor-like mediator for fibroblasts or smooth muscle cells produced and released by activated platelets. Platelet activation occurs with hepatic necrosis and subsequent liver regeneration and fibrosis. In the fibrosis, hepatic stellate cells proliferate with phenotypic transformation to myofibroblasts. Thus, effects of LPA on proliferation of hepatocytes and stellate cells were investigated. In cultured rat stellate cells, LPA increased DNA synthesis with enhanced MAP kinase activity. Pertussis toxin (PTX) attenuated this mitogenic action. In contrast, LPA decreased DNA synthesis by cultured rat hepatocytes induced by hepatocyte growth factor (HGF) or epidermal growth factor (EGF) without affecting protein synthesis. Enhanced MAP kinase activity by HGF or EGF was not changed by LPA. This anti-mitogenic action was attenuated by PTX. TGFbeta level in the medium was less than the level effective for inhibiting the DNA synthesis in the presence of LPA. Our results suggest that LPA might affect proliferation of hepatocytes and stellate cells in liver diseases complicating platelet activation.

Smad6 inhibits signalling by the TGF-beta superfamily.

SMAD proteins have been identified as signalling mediators of the TGF-beta superfamily, which is involved in a range of biological activities including cell growth, morphogenesis, development and immune responses. Smad1, Smad2, Smad3 and Smad5 are ligand-specific: Smadl and Smad5 transduce signals from bone morphogenetic proteins, and Smad2 and Smad3 mediate signalling by TGF-beta and activin, whereas Smad4 acts as a common signalling component. For example, Smad2 is phosphorylated by the TGF-beta type I receptor upon ligand binding, forms a heteromer with Smad4, and then translocates into the nucleus where it activates transcription. Here we report the isolation of Smad6 in the mouse. Smad6 is quite different in structure from the other SMAD proteins, and forms stable associations with type I receptors. Smad6 interferes with the phosphorylation of Smad2 and the subsequent heteromerization with Smad4, but does not inhibit the activity of Smad3. Smad6 also inhibits the phosphorylation of Smad1 that is induced by the bone morphogenetic protein type IB receptor. These data indicate that signals of the TGF-beta superfamily are regulated both positively and negatively by members of the SMAD family.

[Femoral neck and iliac bone histomorphometry in femoral neck fracture].

Involutional osteoporosis is a risk factor for femoral neck fracture in elderly people. This study was designed to evaluate the bone mass and quality of the femoral neck specimen obtained directly from the femoral neck at the time of hip surgery. An iliac bone biopsy was also performed in some cases. A histomorphometric analysis of the femoral neck was performed in 31 women with a femoral neck fracture, aged 64-104 (mean age 76.2), and in 19 women with osteoarthritis of the hip, aged 50-77 (mean age 64.3) as a control. The cortical thickness of the lateral, anterior and posterior aspects of the femoral neck was significantly less in the fracture group than in the osteoarthritis group. However, there was no significant difference in the medial cortical thickness between the two groups. The fracture group exhibited an increased resorption cavity area and intracortical porosity in the cortical area as well as increases in the eroded surface and osteoclast number in the endocortical envelope. The bone volume in the cancellous envelope of the medial femoral neck was significantly lower in the fracture group. Most parameters of the iliac bone were not correlated with those of the femoral neck in either group. Our findings suggested that a femoral neck fracture was associated with a decreased cortical thickness in the femoral neck. Increased intracortical porosity and a low cancellous bone volume were also critical factors in femoral neck fragility, and an iliac bone biopsy did not necessarily reflect the femoral neck bone status.