A comparison of the anabolic effects of rat and bovine parathyroid hormone (1-34) in ovariectomized rats

The current study was designed to compare the skeletal effects of comparable doses of rat parathyroid hormone 1-34 (rPTH) and bovine parathyroid hormone 1-34 (bPTH) in ovariectomized (OVX) rats. Female Sprague-Dawley rats were OVX or sham-operated at 6 months of age and maintained untreated for 28 days after surgery. Baseline control and OVX rats were sacrificed at the beginning of treatment. Beginning 28 days post-OVX, the remaining rats were subcutaneously injected daily with rPTH or bPTH at 0, 5, 25, or 50 microg/kg/d for 28 days. Bone area, bone mineral content (BMC), and bone mineral density (BMD) of the distal femoral metaphyses were determined ex vivo using dual energy X-ray absorptiometry. Quantitative bone histomorphometry was performed on undecalcified longitudinal sections of the proximal tibia from each rat. Baseline OVX rats exhibited osteopenia as demonstrated by their significantly reduced femoral BMD and proximal tibia cancellous bone volume compared with those of baseline sham controls. Both rPTH and bPTH restored bone in OVX rats by markedly stimulating bone formation in a dose-dependent manner. However, a difference in potency between the two forms of PTH was evident. The percentage increases of BMC, BMD, cancellous bone volume, trabecular thickness, mineralizing surface, and bone formation rate in the OVX rats treated with bPTH at 5 microg/kg/d were the same as or above those treated with rPTH at the 25 microg/kg/d dose level. A relative potency analysis showed that bPTH was approximately 4- to 6-fold relatively more potent than rPTH in increasing distal femoral BMD as well as cancellous bone volume, mineralizing surface, and bone formation rate of proximal tibial metaphyses at comparable dose levels and a given time. These results may serve as a reference for in vivo study design when rPTH or bPTH are to be the agents for studies on bone anabolism.     

Effects of spirulina, a blue-green alga, on bone metabolism in ovariectomized rats and hindlimb-unloaded mice

The safety and effectiveness were examined of the spirulina alga on bone metabolism in ovariectomized estrogen-deficient rats and hindlimb-unloaded mice. The dosage range was from an amount equal to that recommended in so-called health foods for humans (0.08 g/kg BW/day) to a 100-fold higher dose. The bone mineral density (BMD) of the whole femur and tibia of ovariectomized rats in the any spirulina-treated groups was not significantly different from that of the ovariectomized group, although BMD of the distal femur and proximal tibia was significantly lower in the spirulina-treated groups than in the ovariectomized group after a 6 week-experimental period. BMD of the femur and tibia was not affected by treatment with any dose of spirulina in hindlimb-unloaded mice. These results suggest that the intake of spirulina decreased BMD in the trabecular bone of rodents under estrogen-deficient conditions.     

Bone mass, bone strength, and their relationship in developing CD-1 mice

Optimizing nutrition during development may provide effective prevention strategies to protect against osteoporosis during later life. Because the mouse model is commonly used to test nutritional interventions on bone health, the overall objective of this study was to determine how bone develops during the first 4 months of life by assessing bone mass (bone mineral content (BMC) and bone mineral density (BMD)) and biomechanical strength properties such as peak load in male and female CD-1 mice. Bone outcomes were assessed at 1 month intervals from 1 to 4 months of age. Femur and spine BMC and BMD at 3 months were similar to 4 months, indicating that the accumulation of bone mass occurs primarily during the first 3 months of life. In contrast, the timing of changes in peak load, a measure of bone strength, varied by skeletal site. Regression analyses demonstrated that femur BMC is a significant predictor of femur peak load at the femur midpoint and neck. The study findings suggest that nutritional interventions aimed at optimizing peak bone mass to prevent osteoporosis may be most effective during pubertal growth.     

中等强度跑台运动预防去卵巢大鼠骨质疏松

目的观察中等强度跑台运动对去卵巢大鼠骨质疏松的预防作用。方法将30只3月龄未经产雌性SD大鼠随机分为假手术、去卵巢静止和去卵巢运动三个组。去卵巢运动组每周进行4次时间45min、速度18m/min、坡度5°的跑台训练。实验结束时,检测血清雌二醇（E2）、碱性磷酸酶（ALP）、抗酒石酸酸性磷酸酶（TRAP）和骨钙素（BGP）水平以及右侧游离股骨和胫骨的骨密度（BMD）和骨矿物含量（BMC）;同时观察左侧股骨远端和胫骨近端组织形态学变化。结果与假手术组比较,去卵巢静止组大鼠血清ALP活性和BGP含量显著升高,血清TRAP活性和E2含量显著下降,股骨近段和远端以及胫骨近端BMD和BMC显著下降,股骨远端和胫骨近端骨小梁断裂增加、数目减少;与去卵巢静止组比较,去卵巢运动组大鼠血清E2和BGP含量显著上升,股骨三个部位以及胫骨近端BMD和BMC显著增加,股骨远端和胫骨近端骨小梁断裂减少、数目增加。结论中等强度跑台运动能增加去卵巢大鼠血清E2和BGP含量,改善去卵巢大鼠骨组织学结构。     

Standardized data and relationship between bone growth and bone metabolism in female G?ttingen minipigs.

Minipigs have been studied as a model of osteoporosis. However, little information is available regarding their bone physiology. We established standardized bone data and investigated the relationship between bone growth and bone metabolism in female minipigs. Blood and urine samples were obtained from 53 female G?ttingen minipigs, 3-76 months of age, for measurement of bone biomarkers (i.e., BAP, OC, NTX, and DPD). The lumbar vertebra and femur were excised to determine the growth plate condition, bone length, bone mineral content (BMC), and bone mineral density (BMD). High levels of bone biomarkers were observed during the initial period after birth, decreasing thereafter with age. Bone biomarkers were confirmed to be highly correlated with age (R(2) > 0.7). The growth plates of the lumbar vertebra and the femur began to close at 21 and 25 months of age, respectively, and closed completely at 42 months of age. Bone length increased rapidly before growth plate closure, and reached a peak at 21 and 28 months of age in the lumbar vertebra and the femur, respectively. The levels of BMC and BMD increased rapidly before growth plate closure, and continued to increase slowly until 76 months of age. A high negative correlation (-0.855 < r < -0.711, p<0.001) was confirmed between the bone biomarkers and the bone measurement data. These results indicate that the bone turnover velocity is consistent with the bone growth velocity in female G?ttingen minipigs.     

Attenuation of bone mass and increase of osteoclast formation in decoy receptor 3 transgenic mice

Decoy receptor 3 (DcR3), a soluble receptor for FasL, LIGHT, and TL1A, induces osteoclast formation from monocyte, macrophage, and bone stromal marrow cells. However, the function of DcR3 on bone formation remains largely unknown. To understand the function of DcR3 in bone formation in vivo, transgenic mice overexpressing DcR3 were generated. Bone mineral density (BMD) and bone mineral content (BMC) of total body were significantly lower in DcR3 transgenic mice as compared with wild-type controls. The difference in BMD and BMC between DcR3 transgenic and control mice was confirmed by histomorphometric analysis, which showed a 35.7% decrease in trabecular bone volume in DcR3 transgenic mice in comparison with wild-type controls. The number of osteoclasts increased in DcR3 transgenic mice. In addition, local administration of DcR3 (30 microg/ml, 10 microl, once/day) into the metaphysis of the tibia via the implantation of a needle cannula significantly decreased the BMD, BMC, and bone volume of secondary spongiosa in tibia. Local injection of DcR3 also increased osteoclast numbers around trabecular bone in tibia. Furthermore, coadminstration of soluble tumor necrosis factor receptor inhibitor/Fc chimera (TNFRSF1A) but not osteoprotegerin inhibited the action of DcR3. In addition, in an assay of osteoclast activity on substrate plates, DcR3 significantly increased the resorption activity of mature osteoclasts. Treatment with higher concentrations of DcR3 slightly increased nodule formation and alkaline phosphatase activity of primary cultured osteoblasts. These results indicate that DcR3 may play an important role in osteoporosis or other bone diseases.     

The calcium-sensing receptor complements parathyroid hormone-induced bone turnover in discrete skeletal compartments in mice

Although the calcium-sensing receptor (CaSR) and parathyroid hormone (PTH) may each exert skeletal effects, it is uncertain how CaSR and PTH interact at the level of bone in primary hyperparathyroidism (PHPT). Therefore, we simulated PHPT with 2 wk of continuous PTH infusion in adult mice with deletion of the PTH gene (Pth(-/-) mice) and with deletion of both PTH and CaSR genes (Pth(-/-)-Casr (-/-) mice) and compared skeletal phenotypes. PTH infusion in Pth(-/-) mice increased cortical bone turnover, augmented cortical porosity, and reduced cortical bone volume, femoral bone mineral density (BMD), and bone mineral content (BMC); these effects were markedly attenuated in PTH-infused Pth(-/-)-Casr(-/-) mice. In the absence of CaSR, the PTH-stimulated expression of receptor activator of nuclear factor-κB ligand and tartrate-resistant acid phosphatase and PTH-stimulated osteoclastogenesis was also reduced. In trabecular bone, PTH-induced increases in bone turnover, trabecular bone volume, and trabecular number were lower in Pth(-/-)-Casr(-/-) mice than in Pth(-/-) mice. PTH-stimulated genetic markers of osteoblast activity were also lower. These results are consistent with a role for CaSR in modulating both PTH-induced bone resorption and PTH-induced bone formation in discrete skeletal compartments.     

Flaxseed oil and inflammation-associated bone abnormalities in interleukin-10 knockout mice

Interleukin-10-/- (IL-10) knockout (KO) mice develop an intestinal inflammation that closely mimics human inflammatory bowel disease (IBD) which is accompanied by inflammation-associated bone abnormalities and elevated serum proinflammatory cytokines. The objective of this study was to use the IL-10 KO mouse model to determine whether flaxseed oil (FO) diet, rich in alpha-linolenic acid (ALA), attenuates intestinal inflammation and inflammation-associated bone abnormalities, compared to a corn oil (CO) control diet. Male wild-type (WT) or IL-10 KO mice were fed a 10% CO or 10% FO diet from weaning (postnatal day 28) for 9 weeks. At necropsy, serum, intestine, femurs and lumbar vertebrae were collected and analyzed. IL-10 KO mice fed CO had lower femur bone mineral content (BMC; P<.001), bone mineral density (BMD; P<.001), peak load (P=.033) and lumbar vertebrae BMD (P=.02) compared to WT mice fed either diet. Flaxseed oil had a modest, favorable effect on IL-10 KO mice as femur BMC, BMD and peak load were similar to WT mice fed CO or FO. In addition, lumbar vertebra BMD was similar among IL-10 KO mice fed FO and WT mice fed CO or FO. The fact that FO attenuated serum tumor necrosis factor-alpha (TNF-alpha) among IL-10 KO mice suggests that the positive effects of FO on femur BMC, BMD, peak load and vertebral BMD in IL-10 KO mice may have been partly mediated by changes in serum TNF-alpha. In conclusion, these findings suggest that a dietary level of ALA attainable from a 10% flaxseed oil diet results in modest improvements in some bone outcomes but does not attenuate intestinal inflammation that is characteristic of IL-10 KO mice.     

Adiponectin is a negative regulator of bone mineral and bone strength in growing mice

Obesity is associated with increased bone mineral density (BMD) but the mechanism for this is unclear. Serum levels of the adipokine adiponectin are inversely correlated with obesity, but results from studies on its relationship to bone mass are conflicting. The objective of this study was to compare bone mineral content (BMC), BMD and biomechanical strength properties of femur and lumbar vertebrae in 8- and 16-week old adiponectin transgenic mice (AdTg). These mice exhibit significantly elevated circulating adiponectin but have similar body weights compared to wild-type (WT) littermates that were used as controls. Female AdTg mice displayed significantly lower femur BMC at 8 and 16 weeks of age and femur neck peak load was significantly lower in 8-week old AdTg mice of both genders compared to controls. The peak load from compression testing of an individual lumbar vertebra was significantly lower in female AdTg mice compared to WT at 8 weeks, and this difference persisted at 16 weeks of age. In addition, lumbar vertebrae BMC was significantly lower in 16-week old male AdTg mice compared to WT although vertebra peak load was not different. Serum adiponectin levels were inversely correlated with femur BMC. In summary, elevated circulating adiponectin inhibits the acquisition of bone mass in growing mice and results in decreased biomechanical measures of functional strength that are surrogate measures of susceptibility to fractures. These results support a role for circulating adiponectin as a metabolic link that can explain, at least in part, the positive relationship between obesity and both bone mass and reduced susceptibility to fractures.     

Effects of growth hormone replacement therapy on bone markers and bone mineral density in growth hormone-deficient adults

During the 1990s, interest in the effects of growth hormone deficiency (GHD) in adults increased, and several studies were performed to evaluate the effects of growth hormone (GH) substitution therapy in these patients. Because adults with GHD have reduced bone mineral density (BMD) and an increased risk of fractures, the effects of GH replacement therapy on bone metabolism have been evaluated in long-term studies. A universal finding is that the serum and urinary levels of biochemical bone markers increase during GH substitution therapy, and these increases are dose dependent. After years of GH substitution therapy, the levels of biochemical bone markers remain elevated, according to some studies, whereas other studies report that these levels return to baseline. BMD of the spine, hip and forearm increase after 18-24 months of treatment. Bone mineral content (BMC) increases to a greater extent than BMD, because the areal projection of bone also increases. This difference could be caused by increased periosteal bone formation, but a measurement artefact resulting from the use of dual-energy X-ray absorptiometry cannot be excluded as a possible explanation. One study of GH-deficient adults found that, after 33 months of GH treatment, BMD and BMC increased to a greater extent in men with GHD than in women. There is also a gender difference in the increases in serum levels of insulin-like growth factor I and biochemical bone markers during GH treatment. The reason for these findings is unknown, and the role of sex steroids in determining the response to GH therapy remains to be fully elucidated.     

Bone densitometry: assessing the effects of growth hormone treatment in adults

Dual-energy X-ray absorptiometry (DXA) is the reference method for the measurement of bone mineral mass at different skeletal sites. It has been widely used in recent years to assess the effects of growth hormone (GH) treatment on bone metabolism. In normal individuals, bone mineral content (BMC) and density (BMD), as assessed using DXA, correlate with body size. Therefore, using DXA in patients with congenital GH deficiency (GHD), who have a smaller body frame, would be expected to result in lower bone mass. Thus, comparisons with reference data derived from populations of normal body size are invalid. The evaluation of the effects of GH administration should take into account the possible effects of GH on bone size, not only in children, but also in adults. The enlargement of bone, due to stimulation of the periosteal apposition, may partially mask an increase in BMC, resulting in little or no change in BMD. The ability of GH to affect bone area therefore requires analysis of the possible changes in bone area and BMC, as well as BMD. This issue has been poorly handled in the studies published to date. Lastly, the acceleration of bone turnover induced by GH leads to an increase in bone remodelling space, which in turn is associated with a reduction in BMC and BMD, independent of the net balance between breakdown and formation in each metabolic unit. This bone loss is completely reversible when the remodelling space returns to previous levels. This phenomenon must be taken into account when analysing the effects of GH treatment on bone mass, because a net gain in bone mass may be found in long-term GH treatment or after GH discontinuation, even if bone loss was evident during the first 6 months of treatment. In conclusion, the interpretation of bone density data in patients with GHD, and after GH administration, should take into account some of the methodological aspects of bone densitometry, as well as the specific actions of GH on bone metabolism and body composition.     

Reduced bone mineral density and radial bone growth in young rabbits treated with dexamethasone eye drops

OBJECTIVE: To investigate the effect of dexamethasone eye drops on bone metabolism in newborn rabbits. METHODS: Thirty-four 3-week-old rabbits had unilateral clear lens extraction and were randomized into three groups. Postoperatively, group 1 received high-dose and group 2 low-dose dexamethasone eye drops (average doses 0.27 and 0.10 mg/kg body weight/day, respectively). These rabbits also received a postoperative subconjunctival injection of betamethasone. Group 3 (control) received vehicle eye drops only. After 8 weeks of treatment, all animals were killed and the left femurs were isolated and subjected to peripheral quantitative computerized tomography (pQCT) and dual X-ray absorptiometry (DXA) analyses. RESULTS: DXA showed that rabbits treated with either a high or low dose of dexamethasone eye drops had significantly reduced areal bone mineral density (BMD), area and total bone mineral content (BMC) of the femur. Measurements with pQCT demonstrated a dose-dependent reduction in cortical BMC, cortical volumetric BMD and cortical area. These effects were associated with an inhibition of radial femur growth, cortical thickness and periosteal and endosteal circumferences. CONCLUSION: Dexamethasone eye drops have systemic effects affecting several bone parameters in young rabbits. Any long-term systemic effects of ocular glucocorticoids need to be further studied.     

In vivo whole body and appendicular bone mineral density in rats: a dual energy X-ray absorptiometry study

Bone mineral density (BMD) of the whole body and hind limb of young adult rats, with and without a sham-operated stifle joint was studied, using dual energy x-ray absorptiometry (DEXA) at three time points. Data from the whole body scan were used for analyses of BMD, bone mineral content (BMC), fat, lean, body weight (BW), percentage of BMC (%BMC), percentage of fat (%fat), and percentage of lean (%lean), none of which were significantly different between the groups at any time point. Significant (P < 0.05) differences in BMD, BMC, %BMC, BW, fat, %fat, and %lean were apparent at the second and third scans, compared with the initial scan, within both groups. Changes in whole body BMD, BMC, and %BMC as well as BW were highly correlated with time in both groups. In the hind limb scans, regions of interest (ROIs) were created to obtain values of BMD and BMC from the whole femur, whole tibia including the fibula, distal portion of the femur, and proximal portion of the tibia. Significant differences were not found between the groups for any ROIs. However, significant BMD and BMC increases were evident in all ROIs at the second and third scans, compared with the initial scan. Similar to those in the whole body scan, BMD and BMC obtained from ROIs were highly correlated with time. The positioning technique for the whole body and appendicular scans was analyzed by calculating percentage of the coefficient of variation (%CV) at the beginning of the study. The %CV was low and acceptable in ROIs for the hind limb and for all parameters of the whole body scan, except fat. The results suggest that in vivo DEXA scanning of the rat whole body and appendicular skeleton is highly reproducible and useful to study the whole skeleton, as well as a region of a long bone of the rat. Values for the sham-operated rats were not significantly different from those for the untreated controls, which suggests that soft tissue damage around the stifle joint did not alter BMD in the subchondral bone of the distal portion of the femur and proximal portion of the tibia.     

Effect of age on bone mineral density and the serum concentration of endogenous nitric oxide synthase inhibitors in rats

Results of previous studies have indicated that bone mineral density (BMD) is decreased in aged animals and elderly humans, and that treatment with nitric oxide (NO) donors prevents bone loss. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, can inhibit NO synthesis. In the study reported here, we examined age-related changes in the serum content of ADMA and in BMD in various skeletal regions. The BMD in the lumbar part of the spine, the femur, and the tibia in 12-month-old rats was markedly increased, compared with that in 6-month-old rats, and the BMD in 20-month-old rats was decreased, compared with that in 12-month-old rats. Serum concentration of ADMA in 20-month-old rats was significantly increased, compared with that in 6- or 12-month-old rats. A similar age-related change in the concentration of lipid peroxide also was seen in the three age groups. These results suggest that the increased amount of endogenous ADMA may be associated with an age-related decrease in BMD in rats.     

Early regional adaptation of periarticular bone mineral density after anterior cruciate ligament injury.

The present study measured early-stage adaptation of bone mineral (BMD) in the periarticular cancellous bone of the canine knee (stifle) joint after anterior cruciate ligament (ACL) transection (ACLX). Regional changes in BMD in the tibia and femur were analyzed by using quantitative computed tomography (qCT) at 3 wk and 12 wk after unilateral ACLX to determine whether there were focal points for BMD changes and whether these changes occurred early after the induced knee injury. BMD decreased rapidly after ACLX, and the more pronounced response was in the femur. In the 3-wk group, there were decreases in BMD in the tibia and the femur, and these changes were significant in the posterior-medial region of the femur, which showed a decrease of BMD in the ACLX limb (-0.048 +/- 0.011 g/cm(3)). In the 12-wk group, all regions in the tibia and femur exhibited significant decreases in BMD, and the average decrease was greatest in the posterior-medial region of the femur (-0.142 +/- 0.021 g/cm(3)). The regions of pronounced periarticular cancellous BMD adaptation corresponded to observed focal cartilage defects. Early decreases in BMD in the injured knee may be related to altered loading and kinematics in the knee and may be an important link in the pathogenesis of posttraumatic osteoarthritis.     

Effect of perinatal synthetic steroid hormone (allylestrenol, diethylstilbestrol) treatment (hormonal imprinting) on the bone mineralization of the adult male and female rat

Neonatal treatment with allylestrenol or diethylstilbestrol (DES) reduced the bone mineral content (BMC/bw) of the adult (four months old) female rats, without influencing bone mineral density (BMD/bw). In males these neonatal treatments elevated BMC and BMD alike. Ovariectomy alone decreased BMC and BMD alike; however the neonatal hormone treatments did not influence this reduced value. Ovariectomy of two months old animals increased body weight without the influence of neonatal hormone treatments. In adult males, the body weight was reduced significantly by neonatal DES and non-significantly by neonatal allylestrenol treatment. The experiments call attention to the possible human bone-effects of allylestrenol, which was used in the last decades as medication protecting endangered pregnancies.     

Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice.

Fibroblast growth factor-23 (FGF-23), a recently identified molecule that is mutated in patients with autosomal dominant hypophosphatemic rickets (ADHR), appears to be involved in the regulation of phosphate homeostasis. Although increased levels of circulating FGF-23 were detected in patients with different phosphate-wasting disorders such as oncogenic osteomalacia (OOM) and X-linked hypophosphatemia (XLH), it is not yet clear whether FGF-23 is directly responsible for the abnormal regulation of mineral ion homeostasis and consequently bone development. To address some of these unresolved questions, we generated a mouse model, in which the entire Fgf-23 gene was replaced with the lacZ gene. Fgf-23 null (Fgf-23-/-) mice showed signs of growth retardation by day 17, developed severe hyperphosphatemia with elevated serum 1,25(OH)2D3 levels, and died by 13 weeks of age. Hyperphosphatemia in Fgf-23-/- mice was accompanied by skeletal abnormalities, as demonstrated by histological, molecular, and various other morphometric analyses. Fgf-23-/-) mice had increased total-body bone mineral content (BMC) but decreased bone mineral density (BMD) of the limbs. Overall, Fgf-23-/- mice exhibited increased mineralization, but also accumulation of unmineralized osteoid leading to marked limb deformities. Moreover, Fgf-23-/- mice showed excessive mineralization in soft tissues, including heart and kidney. To further expand our understanding regarding the role of Fgf-23 in phosphate homeostasis and skeletal mineralization, we crossed Fgf-23-/- animals with Hyp mice, the murine equivalent of XLH. Interestingly, Hyp males lacking both Fgf-23 alleles were indistinguishable from Fgf-23/-/ mice, both in terms of serum phosphate levels and skeletal changes, suggesting that Fgf-23 is upstream of the phosphate regulating gene with homologies to endopeptidases on the X chromosome (Phex) and that the increased plasma Fgf-23 levels in Hyp mice (and in XLH patients) may be at least partially responsible for the phosphate imbalance in this disorder.     

Spared bone mass in rats treated with thyroid hormone receptor TR beta-selective compound GC-1

Thyrotoxicosis is frequently associated with increased bone turnover and decreased bone mass. To investigate the role of thyroid hormone receptor-beta (TR beta) in mediating the osteopenic effects of triiodothyronine (T3), female adult rats were treated daily (64 days) with GC-1 (1.5 microg/100 g body wt), a TR beta-selective thyromimetic compound. Bone mass was studied by dual-energy X-ray absorptiometry of several skeletal sites and histomorphometry of distal femur, and the results were compared with T3-treated (3 microg/100 g body wt) or control animals. As expected, treatment with T3 significantly reduced bone mineral density (BMD) in the lumbar vertebrae (L2-L5), femur, and tibia by 10-15%. In contrast, GC-1 treatment did not affect the BMD in any of the skeletal sites studied. The efficacy of GC-1 treatment was verified by a reduction in serum TSH (-52% vs. control, P < 0.05) and cholesterol (-21% vs. control, P < 0.05). The histomorphometric analysis of the distal femur indicated that T3 but not GC-1 treatment reduced the trabecular volume, thickness, and number. We conclude that chronic, selective activation of the TR beta isoform does not result in bone loss typical of T3-induced thyrotoxicosis, suggesting that the TR beta isoform is not critical in this process. In addition, our findings suggest that the development of TR-selective T3 analogs that spare bone mass represents a significant improvement toward long-term TSH-suppressive therapy.