Citations

Abstract It has been suggested recently that, although fluoride therapy may decrease the occurrence of vertebral fractures, it could increase the risk of hip fractures. To evaluate this possibility, we combined retrospective data from five medical centers that have had a large experience with this therapeutic regimen. In 416 osteoporotic patients who were followed for more than 1,000 patient-years of fluoride treatment, there were 17 nontraumatic hip fractures. This incidence of 1.6% per year is similar to the incidence, 1.9% per year, for 120 of the patients in this series who had been followed prospectively for 3 years prior to initiation of fluoride therapy. The expected incidence for women of the same age in the general community is 0.5% per year. Thus, untreated osteoporotic women are at increased risk for hip fracture, but treatment with fluoride seems neither to decrease nor to increase the incidence of hip fracture substantially.

Abstract Osteoporosis is widely viewed as a major public health concern, but the exact magnitude of the problem is uncertain and likely to depend on how the condition is defined. Noninvasive bone mineral measurements can be used to define a state of heightened fracture risk (osteopenia), or the ultimate clinical manifestation of fracture can be assessed (established osteoporosis). If bone mineral measurements more than 2 standard deviations below the mean of young normal women represent osteopenia, then 45% of white women aged 50 years and over have the condition at one or more sites in the hip, spine, or forearm on the basis of population-based data from Rochester, Minnesota. A smaller proportion is affected at each specific skeletal site: 32% have bone mineral values this low in the lumbar spine, 29% in either of two regions in the proximal femur, and 26% in the midradius. Although this overall estimate is substantial, some other serious chronic diseases are almost as common. More importantly, low bone mass is associated with adverse health outcomes, especially fractures. The lifetime risk of any fracture of the hip, spine, or distal forearm is almost 40% in white women and 13% in white men from age 50 years onward. If the enormous costs associated with these fractures are to be reduced, increased attention must be given to the design and implementation of control programs directed at this major health problem.

Abstract In a 4 year clinical trial in 202 postmenopausal osteoporotic women receiving NaF at 75 mg/day or placebo (both groups received supplementary calcium at 1500 mg/day), we found (N Engl J Med 322:801, 1990) that NaF increased bone mineral density in the lumbar spine (LS-BMD) substantially but did not decrease vertebral fracture rate (VFR), and it increased the nonvertebral fracture rate. Additional analyses and extended observations are now available on 50 women from the NaF group followed for up to 6 years of treatment. In these women, LS-BMD increased linearly over the 6 years (median rate, 8.7%/year or 0.063 g/cm2/year). Because during the 4 year trial the NaF dosage was decreased (because of side effects) in 54 of the 101 women randomized to NaF, dose-response relationships could be evaluated. For the entire study population, serum F level correlated directly with increase in LS-BMD (r = 0.61, P < 0.001). When individual person-years of observation were grouped by deciles of LS-BMD, VFR (per 100 person-years) decreased to a nadir of 24 as mean LS-BMD for the group increased from 0.6 to 1.2 g/cm2 and then doubled to 52 in the group with mean LS-BMD of 1.6 g/cm2. Multivariate analyses and inspection of three-dimensional plots revealed a complex pattern in which VFR was influenced by interaction of several variables. When the effects of LS-BMD, changes in LS-BMD, and serum F were assessed simultaneously, VFR was seen to decrease with increasing LS-BMD except when the higher LS-BMD was associated with rapid rate of increase in LS-BMD or a large increase from baseline serum F. For some patients (noncompliers or nonresponders), serum F or LS-BMD failed to increase. Thus, it is possible that lower dosages of NaF produce moderate decreases in VFR.

Abstract Purpose: Hyperactivation of the phosphatidylinositol 3-kinase/Akt signaling through disruption of PTEN function is common in glioblastoma multiforme, and these genetic changes are predicted to enhance sensitivity to mammalian target of rapamycin (mTOR) inhibitors such as RAD001 (everolimus). Experimental Design: To test whether PTEN loss could be used as a predictive marker for mTOR inhibitor sensitivity, the response of 17 serially transplantable glioblastoma multiforme xenografts was evaluated in an orthotopic therapy evaluation model. Of these 17 xenograft lines, 7 have either genomic deletion or mutation of PTEN. Results: Consistent with activation of Akt signaling, there was a good correlation between loss of PTEN function and elevated levels of Akt phosphorylation. However, of the 7 lines with disrupted PTEN function, only 1 tumor line (GBM10) was significantly sensitive to RAD001 therapy (25% prolongation in median survival), whereas 1 of 10 xenograft lines with wild-type PTEN was significantly sensitive to RAD001 (GS22; 34% prolongation in survival). Relative to placebo, 5 days of RAD001 treatment was associated with a marked 66% reduction in the MIB1 proliferation index in the sensitive GBM10 line (deleted PTEN) compared with a 25% and 7% reduction in MIB1 labeling index in the insensitive GBM14 (mutant PTEN) and GBM15 (wild-type PTEN) lines, respectively. Consistent with a cytostatic antitumor effect, bioluminescent imaging of luciferase-transduced intracranial GBM10 xenografts showed slowed tumor growth without significant tumor regression during RAD001 therapy. Conclusion: These data suggest that loss of PTEN function is insufficient to adequately predict responsiveness to mTOR inhibitors in glioblastoma multiforme.

Abstract Osteoporosis is widely viewed as a major public health concern, but the exact magnitude of the problem is uncertain and likely to depend on how the condition is defined. Noninvasive bone mineral measurements can be used to define a state of heightened fracture risk (osteopenia), or the ultimate clinical manifestation of fracture can be assessed (established osteoporosis). If bone mineral measurements more than 2 standard deviations below the mean of young normal women represent osteopenia, then 45% of white women aged 50 years and over have the condition at one or more sites in the hip, spine, or forearm on the basis of population-based data from Rochester, Minnesota. A smaller proportion is affected at each specific skeletal site: 32% have bone mineral values this low in the lumbar spine, 29% in either of two regions in the proximal femur, and 26% in the midradius. Although this overall estimate is substantial, some other serious chronic diseases are almost as common. More importantly, low bone mass is associated with adverse health outcomes, especially fractures. The lifetime risk of any fracture of the hip, spine, or distal forearm is almost 40% in white women and 13% in white men from age 50 years onward. If the enormous costs associated with these fractures are to be reduced, increased attention must be given to the design and implementation of control programs directed at this major health problem.

Abstract Glucocorticoids (GCs) are commonly used to treat inflammatory disease; unfortunately, the long-term use of these steroids leads to a large number of debilitating side effects. The antiinflammatory effects of GCs are a result of GC receptor (GR)-mediated inhibition of expression of proinflammatory genes as well as GR-mediated activation of antiinflammatory genes. Similarly, side effects are most likely due to both activated and repressed GR target genes in affected tissues. An as yet unachieved pharmaceutical goal is the development of a compound capable of separating detrimental side effects from antiinflammatory activity. We describe the discovery and characterization of AL-438, a GR ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by GCs. When tested in vivo, AL-438 retains full antiinflammatory efficacy and potency comparable to steroids but its negative effects on bone metabolism and glucose control are reduced at equivalently antiinflammatory doses. The mechanism underlying this selective in vitro and in vivo activity may be the result of differential cofactor recruitment in response to ligand. AL-438 reduces the interaction between GR and peroxisomal proliferator-activated receptor γ coactivator-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GR-interacting protein 1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional GCs in treating inflammatory disease.