Appendicular Skeletal Sites Research Articles

Polyethylene particles inserted over calvarium induce cancellous bone loss in femur in female mice

Focal bone resorption (osteolysis) induced by wear particles contributes to long-term orthopedic joint failure. However, the impact of focal osteolysis on remote skeletal sites has received less attention. The goal of this study was to determine the effects of polyethylene particles placed over calvaria on representative axial and appendicular skeletal sites in female mice. Because recent work has identified housing temperature as an important biological variable in mice, response to particle treatment was measured in animals housed at room (22 °C) and thermoneutral (32 °C) temperature. Osteolysis was evident in skeletal tissue adjacent to particle insertion. In addition, cancellous bone loss was observed in distal femur metaphysis. The bone loss was associated with lower osteoblast-lined perimeter and lower mineralizing perimeter in distal femur, lower osteocalcin gene expression in tibia, and lower serum osteocalcin, suggesting the response was due, at least in part, to reduced bone formation. Mild cold stress induced by sub-thermoneutral housing resulted in cancellous bone loss in distal femur and lumbar vertebra but did not influence skeletal response to particles. In summary, the results indicate that focal inflammation induced by polyethylene particles has the potential to result in systemic bone loss. This is significant because bone loss is a risk factor for fracture.

Relative contributions of lean and fat mass to bone strength in young Hispanic and non-Hispanic girls.

With the high prevalence of childhood obesity, especially among Hispanic children, understanding how body weight and its components of lean and fat mass affect bone development is important, given that the amount of bone mineral accrued during childhood can determine osteoporosis risk later in life. The aim of this study was to assess the independent contributions of lean and fat mass on volumetric bone mineral density (vBMD), geometry, and strength in both weight-bearing and non-weight-bearing bones of Hispanic and non-Hispanic girls. Bone vBMD, geometry, and strength were assessed at the 20% distal femur, the 4% and 66% distal tibia, and the 66% distal radius of the non-dominant limb of 326, 9- to 12-year-old girls using peripheral quantitative computed tomography (pQCT). Total body lean and fat mass were measured by dual-energy x-ray absorptiometry (DXA). Multiple linear regression was used to assess the independent relationships of fat and lean mass with pQCT bone measures while adjusting for relevant confounders. Potential interactions between ethnicity and both fat and lean mass were also tested. Lean mass was a significant positive contributor to all bone outcomes (p < 0.05) with the exception of vBMD at diaphyseal sites. Fat mass was a significant contributor to bone strength at weight bearing sites, but did not significantly contribute to bone strength at the non-weight bearing radius and was negatively associated with radius cortical content and thickness. Bone measures did not significantly differ between Hispanic and non-Hispanic girls, although there was a significant interaction between ethnicity and fat mass with total bone area at the femur (p = 0.02) and 66% tibia (p = 0.005) as well as bone strength at the femur (p = 0.03). Lean mass is the main determinant of bone strength for appendicular skeletal sites. Fat mass contributes to bone strength in the weight-bearing skeleton but does not add to bone strength in non-weight-bearing locations and may potentially be detrimental. Bone vBMD, geometry, and strength did not differ between Hispanic and non-Hispanic girls; fat mass may be a stronger contributor to bone strength in weight-bearing bones of Hispanic girls compared to non-Hispanic.

Morphological and molecular characterization of the senile osteoporosis in senescence-accelerated mouse prone 6 (SAMP6).

Although the understanding of the complex pathogenesis for osteoporosis is appreciable, the underlying mechanism is not yet fully elucidated. There is a great need to further characterize the available animal models in osteoporosis research. The senescence-accelerated mouse prone 6 (SAMP6) mice have been developed as the spontaneous experimental model for senile osteoporosis. Here, we provide a comprehensive overview of current research regarding the bone morphological and molecular alterations and the possible mechanisms involved in these changes. There were significant decrease in trabecular bone mass at the axial and appendicular skeletal sites, with no marked alterations of cortical bone. Decreased bone formation on the endosteal surface and trabecular bone, and increased bone marrow adiposity were observed in SAMP6 mice. The elevated expression level of proliferator activator gamma (PPARγ) in the bone marrow suggest that PPARγ might regulate osteoblastic bone formation negatively in SAMP6 mice. The expression level of secreted frizzled-related protein 4 (Sfrp4) was found to be higher in SAMP6 mice. Sfrp4 is considered to suppress osteoblastic proliferation mediated by inhibition of Wnt signaling pathway. These findings may help us to gain more insight into the potential mechanism of senile osteoporosis.

The skeletal site-specific role of connective tissue growth factor in prenatal osteogenesis.

Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that is highly expressed during bone development. Mice with global CTGF ablation (knockout, KO) have multiple skeletal dysmorphisms and perinatal lethality. A quantitative analysis of the bone phenotype has not been conducted. We demonstrated skeletal site-specific changes in growth plate organization, bone microarchitecture, and shape and gene expression levels in CTGF KO compared with wild-type mice. Growth plate malformations included reduced proliferation zone and increased hypertrophic zone lengths. Appendicular skeletal sites demonstrated decreased metaphyseal trabecular bone, while having increased mid-diaphyseal bone and osteogenic expression markers. Axial skeletal analysis showed decreased bone in caudal vertebral bodies, mandibles, and parietal bones in CTGF KO mice, with decreased expression of osteogenic markers. Analysis of skull phenotypes demonstrated global and regional differences in CTGF KO skull shape resulting from allometric (size-based) and nonallometric shape changes. Localized differences in skull morphology included increased skull width and decreased skull length. Dysregulation of the transforming growth factor-β-CTGF axis coupled with unique morphologic traits provides a potential mechanistic explanation for the skull phenotype. We present novel data on a skeletal phenotype in CTGF KO mice, in which ablation of CTGF causes site-specific aberrations in bone formation.

The p38α MAPK positively regulates osteoblast function and postnatal bone acquisition.

Bone continuously remodels throughout life by coordinated actions of osteoclasts and osteoblasts. Abnormalities in either osteoclast or osteoblast functions lead to bone disorders. The p38 MAPK pathway has been shown to be essential in controlling osteoblast differentiation and skeletogenesis. Although p38α is the most abundant p38 member in osteoblasts, its specific individual contribution in regulating postnatal osteoblast activity and bone metabolism is unknown. To elucidate the specific role of p38α in regulating osteoblast function and bone homeostasis, we generated mice lacking p38α in differentiated osteoblasts. Osteoblast-specific p38a knockout mice were of normal weight and size. Despite non-significant bone alterations until 5 weeks of age, mutant mice demonstrated significant and progressive decrease in bone mineral density from that age. Adult mice deficient in p38a in osteoblasts displayed a striking reduction in cancellous bone volume at both axial and appendicular skeletal sites. At 6 months of age, trabecular bone volume was reduced by 62% in those mice. Mutant mice also exhibited progressive decrease in cortical thickness of long bones. These abnormalities correlated with decreased endocortical and trabecular bone formation rate and reduced expressions of type 1 collagen, alkaline phosphatase, osteopontin and osteocalcin whereas bone resorption and osteoclasts remained unaffected. Finally, osteoblasts lacking p38α showed impaired marker gene expressions and defective mineralization in vitro. These findings indicate that p38α is an essential positive regulator of osteoblast function and postnatal bone formation in vivo.

Pharmacodynamic Responses to combined treatment regimens with the calcium sensing receptor antagonist JTT-305/MK-5442 and alendronate in osteopenic ovariectomized rats

Parathyroid hormone (PTH) is the anabolic standard of care for patients with severe osteoporosis. The CaSR allosteric antagonist JTT-305/MK-5442, a PTH secretagogue, could offer an oral osteoanabolic treatment alternative for postmenopausal women with osteoporosis.Here we disclose the pharmacokinetic profile of JTT-305/MK-5442 and its activity on bone remodeling in ovariectomized (OVX) osteopenic rats. Daily treatments (0.3 to 2.4mg/kg/d) for 12weeks resulted in plateaued BMD increases (3.8 to 5.3%) at axial and appendicular skeletal sites. However, treatment effects were not statistically significant, in agreement with effects seen in animals treated with low dose PTH (1–84) (5μg/kg/d).In a consecutive study we tested JTT-305/MK-5442 effects on bone formation in OVX-rats challenged with combined alendronate (ALN) treatment paradigms. At 7month, JTT-305/MK-5442 treatment significantly increased BMD in lumbar vertebrae (LV), while no change in BMD was observed in femora or tibiae. ALN add-on co-treatment produced incremental increases in LV, distal femur (DF) and proximal tibia (PT) BMD over the respective ALN control. Histological analyses confirmed modest increases in mineralized surface (MS/BS) and bone formation rate (30.5±1.9%) on trabecular surfaces by JTT-305/MK-5442. As expected, ALN administration profoundly reduced bone formation, however, JTT-305/MK-5442 significantly stimulated MS/BS and BFR in ALN treated groups.In summary, JTT-305/MK-5442 acts as a PTH secretagogue in the osteopenic OVX-rat, eliciting consistent, though modest effects on remediation of BMD due to estrogen depletion. Induction of bone formation by JTT-305/MK-5442 at trabecular bone surfaces appears to be resilient to ALN-mediated suppression of bone formation. This study provides for the first time, a mechanistic evaluation of combination treatment of a PTH secretagogue with ALN.

Bone mineral densitometry in patients on hemodialysis: difference between genders and what to measure

Introduction: Chronic kidney disease (CKD) and osteoporosis are important health problems. There is an interrelationship between osteoporosis and CKD. Bone densitometry is the “gold” standard in the diagnosis of osteoporosis. Unfortunately, there are some problems with the interpretation of bone densitometry in CKD patients. The goal of this study was to determine bone mineral density (BMD) in CKD patients, to assess the difference between genders and different sites of bone densitometry correlation between BMD and laboratory parameters, and to assess the most optimal measuring site. Methods: We studied 134 hemodialysis (HD) patients (62 females, 72 males). The mean age was 56.4 ± 12.4 years and the mean duration of HD was 54.4 ± 60 months. BMD of the lumbar spine (posterior–anterior projection and lateral projection), hip (femoral neck, trochanter, intertrochanter, total femur, the Ward's Triangle), and forearm (ultradistal (UD), middistal (MID), distal third portion, and total forearm) was measured using dual X-ray absorptiometry (DXA) (Hologic Delphi apparatus). Values were expressed as BMD, T-score, and Z-score. Results: Females had lower values of BMD in all measurement points. There were no significant differences in T- and Z-scores of forearm between males and females. Age was in a positive correlation with lumbar spine BMD in males and females. There was a negative correlation with neck and forearm BMD in both groups. Serum parathyroid hormone (PTH) was also in negative correlation with hip and forearm BMD in both groups. The best correlation of BMD in different sites was between forearm and neck. Conclusion: BMD data in CKD patients should be interpreted with caution and appendicular skeletal sites should be included in the evaluation.

Quantitative computed tomography (QCT) of the forearm using general purpose spiral whole-body CT scanners: Accuracy, precision and comparison with dual-energy X-ray absorptiometry (DXA)

BackgroundDual-energy X-ray absorptiometry (DXA) allows clinically relevant measurement of bone mineral density (BMD) at central and appendicular skeletal sites, but DXA has a limited ability to assess bone geometry and cannot distinguish between the cortical and trabecular bone compartments. Quantitative computed tomography (QCT) can supplement DXA by enabling geometric and compartmental bone assessments. Whole-body spiral CT scanners are widely available and require only seconds per scan, in contrast to peripheral QCT scanners, which have restricted availability, limited spatial resolution, and require several minutes of scanning time.This study evaluated the accuracy and precision of whole-body spiral CT scanners for quantitatively assessing the distal radius, a common site of non-vertebral osteoporosis-related fractures, and compared the CT-measured densitometric values with those obtained from dual-energy-X-ray absorptiometry. Subjects and methodsA total of 161 postmenopausal women with baseline lumbar spine BMD T-scores between −1.0 and −2.5 underwent left forearm QCT using whole-body spiral CT scanners twice, 1 month apart. QCT volumes of interest were defined and analyzed at 3 specific radial regions: the ultradistal region by using slices at 8, 9, and 10 mm proximal to the ulnar styloid tip; the distal region by a slice 20 mm proximal; and the middle region by a slice 40 mm proximal. BMD, bone mineral content (BMC), volume, and average cortical thickness and circumference were measured. We evaluated QCT accuracy and precision and also report correlations between QCT and DXA for BMD and BMC. ResultsOverall accuracy and precision errors for BMD, BMC and volume were consistent with known skeletal QCT technology precision and were generally less than 3%. BMD and BMC assessed by QCT and DXA were correlated (r=0.55 to 0.80). DiscussionWhole-body spiral CT scanners allow densitometric evaluations of the distal radius with good accuracy and very good precision. This original and convenient method provides a tool to further investigate cortical and trabecular bone variables in the peripheral skeleton in osteoporotic patients. These assessments, coupled with evaluation of the effects on cortical and trabecular bone measured in response to therapies for osteoporosis, may advance our understanding of the contributors to non-vertebral fracture occurrence.

A comparison of bone mineral density in oligomenorrhoeic adolescents with polycystic ovaries and normal ovaries

We evaluated whether the presence of polycystic ovaries in adolescent girls as a cause of oligomenorrhoea and amenorrhoea would pose any protective effect against osteoporosis or low bone mineral density (BMD) compared with girls having similar menstrual dysfunction but normal ovaries. A cross-sectional observational study was done in consecutive girls, aged between 16 and 19 years, presenting to the adolescent gynaecology clinic with oligomenorrhoea or amenorrhoea. All patients underwent full hormonal profile assessment, pelvic ultrasound for ovarian morphology, bio-impedance estimation of body fat, and dual-energy X-ray absorptiometry and quantitative peripheral computed tomography scans to determine BMD in axial and appendicular skeletal sites. Polycystic ovaries were diagnosed according to ultrasound morphology. These were then compared with an age-matched eumenorrhoeic control group that had undergone the same evaluation. Of 45 patients with oligomenorrhoea or amenorrhoea, 14 (31%) were diagnosed to have polycystic ovaries, while the other 31 had normal ovaries. The control group consisted of 45 age-matched eumenorrhoeic girls. The group with normal ovaries had lower BMD at the lumbar spine and hip, as well as lower total tibial volumetric BMD, than the eumenorrhoeic controls, but there were no significant differences between the group with polycystic ovaries and eumenorrhoeic controls. We conclude that adolescents with oligomenorrhoea and amenorrhoea with normal ovaries had lower BMD than eumenorrhoeic ones, but those with polycystic ovaries had BMD values comparable to those of eumenorrhoeic controls despite their menstrual dysfunction.

Skeletal Site Selectivity in the Effects of Calcium Supplementation on Areal Bone Mineral Density Gain: A Randomized, Double-Blind, Placebo-Controlled Trial in Prepubertal Boys

Calcium supplementation during childhood and adolescence is considered an early means of preventing osteoporosis in adults. Prepuberty is an opportune time for detecting the benefits of calcium in girls. The objective was to assess whether calcium supplementation increases bone mass gain in prepubertal boys in a skeletal site-specific manner. In a 12-month double-blind, placebo-controlled trial with 1-yr follow-up, 235 healthy prepubertal boys aged 7.4 +/- 0.4 yr (mean +/- sd) were randomized to receive two food products providing 850 mg/d calcium (calcium supplement group, n = 116) or an isocaloric placebo (n = 119). Areal bone mineral density (aBMD) was determined by dual-energy x-ray absorptiometry at radius (two sites), hip (two sites), femoral diaphysis (FDia), and L2-L4 vertebrae. At 12 months, aBMD gain was greater at the FDia and at the mean of the five appendicular skeletal sites in the calcium supplement group in both intention-to-treat analysis [76 +/- 32 vs. 64 +/- 33 mg/cm(2).yr; difference, 12.0 (95% confidence interval, CI, 3.6-20.3), P = 0.006; and 33 +/- 16 vs. 28 +/- 16 mg/cm(2).yr; difference, 5.1 (95% CI, 0.9-9.2); P = 0.018, respectively] and active treatment analysis [81 +/- 32 vs. 64 +/- 31 mg/cm(2).yr; difference, 17.2 (95% CI, 7.9-26.5); n = 174, P < 0.001; and 35 +/- 16 vs. 28 +/- 14 mg/cm(2).yr; difference, 7.5 (95% CI, 2.9-12.2); P = 0.002]. There was no beneficial effect of calcium on lumbar spine. The calcium effect was still detectable by ANOVA repeated measures analysis at the FDia (P = 0.004) and at the mean of the five appendicular skeletal sites (P = 0.002) 1 yr after the end of intervention (active treatment analysis). There was no change in bone size. In prepubertal boys, calcium-enriched foods increased aBMD at several appendicular skeleton sites, but not at the lumbar spine, and this without any bone size change. This effect was maintained 1 yr after treatment discontinuation.

Bone Density in Axial and Appendicular Skeleton in Patients with Lactose Intolerance: Influence of Calcium Intake and Vitamin D Status

Background: Lactose intolerance (LI) is a common enzymatic insufficiency, manifesting by poor tolerance of dairy products, leading to low calcium intake and poor calcium absorption from dairy products. These changes might lead to an impairment of bone metabolism [1].Objectives: To evaluate the impact of LI on quantitative bone parameters in axial and appendicular skeletal sites. To assess the impact of calcium intake from dairy and non-dairy nutritional sources, calcium regulating hormones and bone turnover on quantitative bone parameters in LI patients.Methods: We evaluated calcium intake and bone status in sixty-six patients with LI, 49 women and 17 men, aged 20 to 78. Bone mass was assessed at the lumbar spine (LS), total hip (TH) and femoral neck (FN) by dual-energy x-ray absorptiometry (DEXA) and at the radius, tibia, phalanx by quantitative ultrasound. Serum calcium, albumin, inorganic phosphate, calcium regulating hormones and markers of bone turnover were evaluated.Results: Total daily calcium intake was below the recommended by the American Dietetic Association [2] in all study participants (mean 692 mg/day ± 162). Elevated level of urinary deoxypyridinoline crosslinks (DPD) was observed in 63 (96%) patients and was negatively correlated with total daily calcium intake (r = −0.998, p = 0.025) and with nondairy calcium intake (r = −0.34, p = 0.015). Parathyroid hormone (PTH) level in the upper third of normal range (45–65 ng/L) was observed in 11 (17%) patients. Parathyroid hormone (PTH) was inversely correlated with total calcium intake (r = −0.4, p = 0.001), dairy calcium intake (r = −0.83, p = 0.05), non-dairy calcium intake (r = −0.29, p = 0.043), 25OHD3 serum level (r = −0.3, p = 0.007) and positively correlated with bone turnover markers (deoxypyridinoline crosslinks [DPD], r = 0.36, p = 0.01 and bone specific alkaline phosphatase [BSAP] r = 0.36, p = 0.01). Decrease in quantitative bone parameters compared to age-matched controls was observed in the axial and in the appendicular skeleton in men and in postmenopausal women: mean z-score for LS −0.87 ± 0.22 and −1.32 ± 0.65, p = 0.004 and 0.015, tibia −1.15 ± 0.53 and −0.44 ± 0.044, p < 0.001 and 0.27, phalanx −0.98 ± 0.22 and −0.52 ± 0.98, p < 0.001. We observed decrease in bone mass in patients with serum PTH in the upper tertile of normal range in the FN (z-score −0.57 ± 0.6 versus −0.03 ± 0.9, p = 0.025), TH (−0.51 ± 0.96 versus 0.04 ± 0.9, p = 0.05) and radius (−1.84 ± 0.27 versus −0.07 ± 1.61, p = 0.025, respectively). z-scores in FN and TH positively correlated with serum 25OHD3 level (r = 0.31, 0.29; p = 0.014, 0.019). In postmenopausal women serum 25OHD3 level correlated also with LS z-scores (r = 0.52, p = 0.004); FN and TH z-scores negatively correlated with DPD level (r = −0.51, p = 0.02 and r = −0.55, p = 0.04).Conclusion: LI state may lead to increased bone turnover and decreased bone mass especially in men and postmenopausal women. Impaired vitamin D status and low calcium intake may be deleterious to bone in this condition.

Anabolic action of parathyroid hormone on cortical and cancellous bone differs between axial and appendicular skeletal sites in mice

The mouse is being increasingly used to study the anabolic action of parathyroid hormone (PTH) on the skeleton. The efficacy of intermittent PTH treatment on bone varies widely among tested strains of mice with differences in peak bone mass and structure. We have therefore examined the responses of skeletal sites with high or low cancellous bone mass to PTH treatment in a single strain with genetically low bone mass. Mature C57BL/6 mice were ovariectomized (ovx) or sham operated and, after 4 weeks, treated with PTH(1–34) (40 μg/kg/day, 5 days/week sc) or vehicle for 3 or 7 weeks. Two doses of fluorescent labels were given to the animals 9 and 3 days before euthanasia. Histomorphometry was performed on sections of the proximal tibia, tibial diaphysis, and vertebral body. The results indicate that 4 to 11 weeks of ovx induced a ∼44% loss of cancellous bone in the proximal tibia and a ∼25% loss of cancellous bone in the vertebra with impaired trabecular architecture and high bone turnover. In the intact animals, PTH increased cancellous bone volume to a greater extent in the vertebral body than in the proximal tibia, a site with lower cancellous bone volume at the outset. In the ovx mice, PTH increased cancellous bone volume to a greater extent in the vertebral body, a site displaying moderate cancellous bone loss, than in the proximal tibia, a site with severe cancellous bone loss. Conversely, the treatment added a little cortical bone to the tibia, a highly loaded site, but did not significantly increase cortical width of the vertebral body, a less loaded site. We conclude that, for intermittent PTH treatment to be maximally effective, there must be an adequate number of trabeculae present at the beginning of treatment, regardless of estrogen status. Our results also support an interaction between PTH anabolic action and mechanical loading.

Additive effect of voluntary exercise and growth hormone treatment on bone strength assessed at four different skeletal sites in an aged rat model

The aim of the study was to assess the effect of growth hormone (GH), voluntary exercise (Ex), and the combination of GH and Ex on bone strength, mass, and dimensions in aged, intact female rats. In addition, the effect of food restriction (FR) was studied. Fourteen-month-old virgin F-344 rats were divided into 6 groups with 13 animals in each: (1) baseline (BSL); (2) control + solvent vehicle (CTRL); (3) GH 2.5 mg/kg/day (GH); (4) exercise, voluntary: 0.6–0.7 km/day (Ex); (5) GH treatment and voluntary exercise (GH + Ex); and (6) FR. Group 1 was killed at the beginning of the study and served as baseline. All the other groups were killed after 18 weeks’ treatment. The effects of aging and treatment regimes were measured at four different skeletal sites: lumbar vertebrae, femoral cortical bone, femoral neck, and the distal femoral metaphysis. Aging in itself induced a decline in vertebral body strength and ash density. At the appendicular skeletal sites, bone mass and strength were unchanged or increased. Treatment with GH alone induced a significant increase in the biomechanical parameters at the vertebral body and the femoral diaphysis, but not at the femoral neck or the distal femoral metaphysis. Voluntary exercise on its own increased load values significantly over CTRL at the vertebral body site, but not at any of the appendicular skeletal sites. The combination of GH and voluntary exercise resulted in an additive effect at the vertebral site and at the femoral diaphysis, and a synergistic (potentiating) effect at the two femoral metaphyses. FR, on the other hand, had a negative effect on cortical bone area and strength at the femoral diaphysis, but no significant effect on the other sites tested. We conclude that GH treatment and voluntary exercise both have skeletal anabolic effects; however, these effects are exerted to differing degrees at different sites. Importantly, when dosed together, GH and Ex have either an additive or synergistic anabolic effect on all sites (axial and appendicular).

Biosynthetic human parathyroid hormone (1-34) effects on bone quality in aged ovariectomized rats.

For the first time, PTH (1-34) was found to significantly affect bone quality, femora length, and body weight of aged, ovariectomized rats. Specifically, we examined the effects of biosynthetic human PTH (1-34) in 9 month-old rats that were ovariectomized and dosed for the ensuing 6 months with 8 or 40 microg/kg PTH. Bone content, architecture, and quality of axial and appendicular skeletal sites were analyzed by computed tomography (QCT), histomorphometry, and biomechanical testing. The large sample size (n = 26-35) of this study was useful in confirming the anabolic, dose-dependent effects of PTH at trabecular and cortical bone sites. Longitudinal analysis of tibias by QCT confirmed a small age-dependent reduction in bone density, with further reductions observed for ovariectomized controls (OVX). Subtle but deleterious effects of ovariectomy on bone quality are described. Additionally, the strength of the femoral neck was shown not to differ between baseline, sham-operated controls, or OVX in this model, suggesting limited utility of this measurement in aged rats. Both doses of PTH induced substantial gains above OVX, in bone mass and connectivity for the proximal tibia, distal femur, proximal femur, and spine. Ovariectomy significantly decreased the toughness of vertebral bone. However, PTH at 8 microg/kg reversed this deleterious effect on bone quality, while 40 microg/kg PTH significantly improved both toughness and brittleness beyond baseline controls. Cortical bone analyses at the femoral or tibial diaphysis confirmed the PTH stimulation of endosteal and periosteal bone formation with resulting increase in cortical thickness, moment of inertia, strength, and stiffness of the femur. PTH treatment significantly improved the intrinsic properties, Young's modulus and toughness, of the femur compared with OVX. At 40 microg/kg PTH, bone mass and strength were typically greater than sham or baseline controls, confirming that PTH is functionally anabolic at trabecular and cortical bone sites. Interestingly, PTH dose-dependently increased the femora length, in the absence of differences between baseline, sham, and OVX controls. PTH slightly increased body weight above OVX. In addition, PTH did not interfere with the beneficial effects of ovariectomy on rat longevity.