Thyroid hormone (T3) has widespread functions in development and homeostasis, although the receptor pathways by which this diversity arises are unclear. Deletion of the T3 receptors TRα1 or TRβ individually reveals only a small proportion of the phenotypes that arise in hypothyroidism, implying that additional pathways must exist. Here, we demonstrate that mice lacking both TRα1 and TRβ (TRα1 ^−/− β ^−/−) display a novel array of phenotypes not found in single receptor-deficient mice, including an extremely hyperactive pituitary–thyroid axis, poor female fertility and retarded growth and bone maturation. These results establish that major T3 actions are mediated by common pathways in which TRα1 and TRβ cooperate with or substitute for each other. Thus, varying the balance of use of TRα1 and TRβ individually or in combination facilitates control of an extended spectrum of T3 actions. There was no evidence for any previously unidentified T3 receptors inTRα1 ^−/− β ^−/−mouse tissues. Compared to the debilitating symptoms of severe hypothyroidism, the milder overall phenotype ofTRα1 ^−/− β ^−/−mice, lacking all known T3 receptors, indicates divergent consequences for hormone versus receptor deficiency. These distinctions suggest that T3-independent actions of T3 receptors, demonstrated previously in vitro, may be a significant function in vivo.

The osteoblast-derived protein osteocalcin has recently been shown to affect adiposity and glucose homeostasis in mice, suggesting that the skeleton influences energy metabolism through an endocrine mechanism. The aim of this study was to investigate the relationship between plasma osteocalcin and parameters reflecting fat mass and glucose homeostasis in humans. Fasting levels of plasma osteocalcin, plasma glucose, serum insulin, and lipids were analyzed in elderly men (75.3 ± 3.2 yr of age) in the Gothenburg part (all subjects, n = 1010; nondiabetic, n = 857; diabetic, n = 153) of the MrOS Sweden study. Fat mass and lean mass were analyzed using DXA. Diabetic subjects had lower plasma osteocalcin (−21.7%, p < 0.001) than nondiabetic subjects. For both all subjects and nondiabetic subjects, plasma osteocalcin was clearly inversely related to body mass index (BMI), fat mass, and plasma glucose (p < 0.001), whereas it was not associated with height or lean mass. Plasma osteocalcin explained a substantial part (6.3%) of the variance in plasma glucose, whereas it associated moderately with serum insulin. Multiple linear regression models adjusting for serum insulin and fat mass showed that plasma osteocalcin was an independent negative predictor of plasma glucose (p < 0.001). We herein, for the first time in humans, show that plasma osteocalcin is inversely related to fat mass and plasma glucose. Although one should be cautious with mechanistic interpretations of cross-sectional association studies, our human data support recently published experimental studies, showing endocrine functions of osteoblast-derived osteocalcin on glucose and fat homeostasis.

Most patients with the syndrome resistance to thyroid hormone (RTH) express a mutant thyroid hormone receptor β (TRβ) with transdominant negative transcriptional effects. Since no patient with a mutant TRα has been identified, we introduced a point mutation into the mouse thyroid hormone receptor (TRα1) locus originally found in the TRβ gene, that reduces ligand binding 10‐fold. Heterozygous 2‐ to 3‐week‐ old mice exhibit a severe retardation of post‐natal development and growth, but only a minor reduction in serum thyroxine levels. Homozygous mice died before 3 weeks of age. Adult heterozygotes overcome most of these defects except for cardiac function abnormalities, suggesting that other factors compensate for the receptor defect. However, the additional deletion of the TRβ gene in this mouse strain caused a 10‐fold increase in serum thyroxine, restored hormonal regulation of target genes for TRs, and rescued the growth retardation. The data demonstrate a novel array of effects mediated by a dominant negative TRα1, and may provide important clues for identification of a potentially unrecognized human disorder and its treatment.

The bone-sparing effect of estrogen in both males and females is primarily mediated via estrogen receptor-α (ERα), encoded by the Esr1 gene. ERα in osteoclasts is crucial for the trabecular bone-sparing effect of estrogen in females, but it is dispensable for trabecular bone in male mice and for cortical bone in both genders. We hypothesized that ERα in osteocytes is important for trabecular bone in male mice and for cortical bone in both males and females. Dmp1-Cre mice were crossed with ERα ^flox/flox mice to generate mice lacking ERα protein expression specifically in osteocytes ( Dmp1-ERα ^−/− ). Male Dmp1-ERα ^−/− mice displayed a substantial reduction in trabecular bone volume (−20%, P < 0.01) compared with controls. Dynamic histomorphometry revealed reduced bone formation rate (−45%, P < 0.01) but the number of osteoclasts per bone surface was unaffected in the male Dmp1-ERα ^−/− mice. The male Dmp1-ERα ^−/− mice had reduced expression of several osteoblast/osteocyte markers in bone, including Runx2 , Sp7 , and Dmp1 ( P < 0.05). Gonadal intact Dmp1-ERα ^−/− female mice had no significant reduction in trabecular bone volume but ovariectomized Dmp1-ERα ^−/− female mice displayed an attenuated trabecular bone response to supraphysiological E2 treatment. Dmp1-ERα ^−/− mice of both genders had unaffected cortical bone. In conclusion, ERα in osteocytes regulates trabecular bone formation and thereby trabecular bone volume in male mice but it is dispensable for the trabecular bone in female mice and the cortical bone in both genders. We propose that the physiological trabecular bone-sparing effect of estrogen is mediated via ERα in osteocytes in males, but via ERα in osteoclasts in females.

The bone-sparing effect of estrogen is primarily mediated via estrogen receptor-α (ERα), which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand binding domain. To evaluate the role of ERα AF-1 and ERα AF-2 for the effects of estrogen in bone in vivo, we analyzed mouse models lacking the entire ERα protein (ERα ^−/− ), ERα AF-1 (ERαAF-1 ⁰ ), or ERα AF-2 (ERαAF-2 ⁰ ). Estradiol (E2) treatment increased the amount of both trabecular and cortical bone in ovariectomized (OVX) WT mice. Neither the trabecular nor the cortical bone responded to E2 treatment in OVX ERα ^−/− or OVX ERαAF-2 ⁰ mice. OVX ERαAF-1 ⁰ mice displayed a normal E2 response in cortical bone but no E2 response in trabecular bone. Although E2 treatment increased the uterine and liver weights and reduced the thymus weight in OVX WT mice, no effect was seen on these parameters in OVX ERα ^−/− or OVX ERαAF-2 ⁰ mice. The effect of E2 in OVX ERαAF-1 ⁰ mice was tissue-dependent, with no or weak E2 response on thymus and uterine weights but a normal response on liver weight. In conclusion, ERα AF-2 is required for the estrogenic effects on all parameters evaluated, whereas the role of ERα AF-1 is tissue-specific, with a crucial role in trabecular bone and uterus but not cortical bone. Selective ER modulators stimulating ERα with minimal activation of ERα AF-1 could retain beneficial actions in cortical bone, constituting 80% of the skeleton, while minimizing effects on reproductive organs.

Aims: Medication reviews by a third party have been introduced as a method to improve drug treatment in older people. We assessed whether this intervention reduces mortality and hospitalization for nursing home residents.Methods: Systematic literature searches were performed (from January 1990 to June 2012) in Medline, EMBASE, Cochrane Library, ProQuest Nursing & Allied Health Sources and Health Technology Assessment databases. We included randomized and nonrandomized controlled trials (RCTs and non‐RCTs) of medication reviews compared with standard care or other types of medication reviews in nursing home residents. The outcome variables were mortality and hospitalization. Study quality was assessed systematically. We performed meta‐analyses using random‐effects models.Results: Seven RCTs and five non‐RCTs fulfilled the inclusion criteria. The mean age of included patients varied between 78 and 86 years. They were treated with a mean of 4–12 drugs. The study quality was assessed as high (n = 1), moderate (n = 4) or low (n = 7). Eight studies compared medication reviews with standard care. In six of them, pharmacists were involved in the intervention. Meta‐analyses of RCTs revealed a risk ratio (RR) for mortality of 1.03 [medication reviews vs. standard care; five trials; 95% confidence interval (CI) 0.85–1.23]. The corresponding RR for hospitalization was 1.07 (two trials; 95% CI 0.61–1.87).Conclusions: Our findings indicate that medication reviews for nursing home residents do not reduce mortality or hospitalization. More research in the setting of controlled trials remains to be done in order to clarify how drug treatment can be optimized for these patients.