ABSTRACT:We assessed the effects on bone remodeling and histomorphometry after daily subcutaneous injections of teriparatide (n = 39, 20 mg/d) or oral strontium ranelate (SrR, n = 40, 2 g/d) in postmenopausal women with osteoporosis. Evaluable biopsies were obtained from 29 patients in the teriparatide group and 22 in the SrR group after 6 mo of treatment. The mean ± SD mineralization surfaces as a percent of bone surfaces (MS/BS, %) at the trabecular level were 7.73 ± 1.48% for teriparatide and 5.25 ± 1.15% for SrR (p = 0.219) and at the endocortical level were 17.22 ± 3.06% and 9.70 ± 2.07%, respectively (p = 0.052). Cortical porosity was 5.40 ± 0.41% in the teriparatide and 4.14 ± 0.40% in the SrR group (p = 0.037). Teriparatide induced significant increases from baseline in bone formation and resorption markers, reaching statistical significance for amino-terminal propeptide of type I collagen (PINP) after 1 mo (+57%, p < 0.001). SrR induced small, but statistically significant, reductions from baseline in PINP at 3 (214%, p = 0.005) and 6 mo (219%, p < 0.001) and in serum b-C-terminal telopeptide of type I collagen (b-CTX) at 1 and 3 mo (211%, for both, p < 0.05). There were more patients with adverse events after SrR (70%) than teriparatide (41%) treatment (p = 0.013). In conclusion, the changes in biochemical markers of bone formation confirmed bone-forming activity of teriparatide but not of SrR treatment. The effects of SrR on bone remodeling and cell activity were modest, indicating that its effects on fracture reduction may be predominantly mediated through a different mechanism than that observed with anabolic or more potent antiresorptive agents.

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The effects of progesterone on oophorectomy-induced bone loss in aged rats were evaluated. Female rats aged 12 months were divided into three groups: (1) sham-operated controls (SHAM); (2) oophorectomized (OVX); (3) OVX rats treated with progesterone (OVX + PROG). After 20 weeks the dry weight, bone ash, and calcium content of femur, tibia, and fourth lumbar vertebra were significantly lower in OVX than in sham rats. These reductions did not occur in OVX rats treated with PROG. There was no difference in the bone composition between the control and progesterone-treated rats. Vertebral bone histomorphometry showed increased bone resorption as well as increased bone formation parameters in OVX rats. Progesterone treatment inhibited the increased resorption indices, but the bone formation remained elevated. The results indicate that progesterone therapy prevents the postovariectomy bone loss in aged rats. The protective effect of progesterone is mediated by inhibition of bone resorption while maintaining the increased bone formation. These findings suggest that progesterone alone may be a valuable agent for management of postmenopausal osteoporosis.

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generated by crossing B6.Cg-Tg(Lck-cre)548Jxm/J with Rictor tm1.1Klg /SjmJ. RESULTS: In a syngeneic mouse prostate cancer model, ezetimibe decreased serum cholesterol level, increased infiltration of CD8þ lymphocytes into tumor, and inhibited tumor growth in a CD8þ lymphocyte-dependent manner. Ezetimibe-treatment was associated with an increase in markers of central memory lymphocytes such as CD44, CD62L and Eomes. Pmel-1 transgenic mice have CD8þ lymphocytes that recognize a tumor antigen and can be transferred into WT mice to monitor tumor-specific CD8þ lymphocyte expansion and function. In ezetimibe-treated mice, immune stimulation produced Pmel-1 lymphocytes with central memory phenotype, and greater capacity to expand and protect against tumor. mTOR can complex with raptor to form mTORC1 or Rictor to form mTORC2. In lymphocytes, CL decreased phosphorylation of AKT (Ser473), which is associated with mTORC2 signaling. Conditional KO mice with T lymphocyte specific Rictor KO had enhanced CD8þ lymphocyte function, decreased tumor growth, and enhanced CD8þ lymphocyte memory when compared to control mice and these effects were not further enhanced with CL.CONCLUSIONS: CL inhibited tumor growth by modulating immunity. CL enhanced tumor specific CD8þ lymphocytes, which had enhanced memory function and infiltrated tumor. Enhanced CD8þ lymphocyte function was due to inhibition of mTOR2 signaling in mouse lymphocytes. Our results provide additional justification for formal clinical testing of CL intervention for primary or secondary chemoprevention and as a strategy to enhance the effects of immunotherapies for advanced prostate tumors.