Abstract: Introduction: Sclerosteosis is a rare high bone mass genetic disorder in humans caused by inactivating mutations in SOST, the gene encoding sclerostin. Based on these data, sclerostin has emerged as a key negative regulator of bone mass. We generated SOST knockout (KO) mice to gain a more detailed understanding of the effects of sclerostin deficiency on bone. Materials and Methods: Gene targeting was used to inactivate SOST and generate a line of SOST KO mice. Radiography, densitometry, μCT, histomorphometry, and mechanical testing were used to characterize the impact of sclerostin deficiency on bone in male and female mice. Comparisons were made between same sex KO and wildtype (WT) mice. Results: The results for male and female SOST KO mice were similar, with differences only in the magnitude of some effects. SOST KO mice had increased radiodensity throughout the skeleton, with general skeletal morphology being normal in appearance. DXA analysis of lumbar vertebrae and whole leg showed that there was a significant increase in BMD (>50%) at both sites. μCT analysis of femur showed that bone volume was significantly increased in both the trabecular and cortical compartments. Histomorphometry of trabecular bone revealed a significant increase in osteoblast surface and no significant change in osteoclast surface in SOST KO mice. The bone formation rate in SOST KO mice was significantly increased for trabecular bone (>9-fold) at the distal femur, as well as for the endocortical and periosteal surfaces of the femur midshaft. Mechanical testing of lumbar vertebrae and femur showed that bone strength was significantly increased at both sites in SOST KO mice. Conclusions:SOST KO mice have a high bone mass phenotype characterized by marked increases in BMD, bone volume, bone formation, and bone strength. These results show that sclerostin is a key negative regulator of a powerful, evolutionarily conserved bone formation pathway that acts on both trabecular and cortical bone.

Abstract: Context: Rates of bone loss across the menopause transition and factors associated with variation in menopausal bone loss are poorly understood. Objective: Our objective was to assess rates of bone loss at each stage of the transition and examine major factors that modify those rates. Design, Setting, and Participants: We conducted a longitudinal cohort study of 1902 African-American, Caucasian, Chinese, or Japanese women participating in The Study of Women’s Health Across the Nation. Women were pre- or early perimenopausal at baseline. Outcome Measure: We assessed bone mineral density (BMD) of the lumbar spine and total hip across a maximum of six annual visits. Results: There was little change in BMD during the pre- or early perimenopause. BMD declined substantially in the late perimenopause, with an average loss of 0.018 and 0.010 g/cm2·yr from the spine and hip, respectively (P < 0.001 for both). In the postmenopause, rates of loss from the spine and hip were 0.022 and 0.013 g/cm2·yr, respectively (P ...

Abstract: Context: Primary hyperparathyroidism (PHPT) often presents without classical symptoms such as overt skeletal disease or nephrolithiasis. We previously reported that calciotropic indices and bone mineral density (BMD) are stable in untreated patients for up to a decade, whereas after parathyroidectomy, normalization of biochemistries and increases in BMD ensue. Objective: The objective of the study was to provide additional insights in patients with and without surgery for up to 15 yr. Design: The study had an observational design. Setting: The setting was a referral center. Patients: Patients included 116 patients (25 men, 91 women); 99 (85%) were asymptomatic. Intervention: Fifty-nine patients (51%) underwent parathyroidectomy and 57 patients were followed up without surgery. Main Outcome Measure: BMD was measured. Results: Lumbar spine BMD remained stable for 15 yr. However, BMD started to fall at cortical sites even before 10 yr, ultimately decreasing by 10 ± 3% (mean ± sem; P < 0.05) at the femoral ne...

Abstract: Body weight impacts both bone turnover and bone density, making it, therefore, an important risk factor for vertebral and hip fractures and ranking it alongside age in importance. The effect of body weight is probably contributed to by both fat mass and lean mass, though in postmenopausal women, fat mass has been more consistently demonstrated to be important. A number of mechanisms for the fat-bone relationship exist and include the effect of soft tissue mass on skeletal loading, the association of fat mass with the secretion of bone active hormones from the pancreatic beta cell (including insulin, amylin, and preptin), and the secretion of bone active hormones (e.g., estrogens and leptin) from the adipocyte. These factors alone probably do not fully explain the observed clinical associations, and study of the actions on bone of novel hormones related to nutrition is an important area of further research. An understanding of this aspect of bone biology may open the way for new treatments of osteoporosis. More immediately, the role of weight maintenance in the prevention of osteoporosis is an important public health message that needs to be more widely appreciated.

Abstract: This systematic review of 76 randomized trials and 24 meta-analyses found good evidence that several agents, including alendronate, zoledronic acid, and estrogen, reduced the risk for vertebral and...

Abstract: Osteoporosis is an important systemic disorder, affecting mainly Caucasian women, with a diverse and multifactorial etiology. A large variety of animal species, including rodents, rabbits, dogs, and primates, have been used as animal models in osteoporosis research. Among these, the laboratory rat is the preferred animal for most researchers. Its skeleton has been studied extensively, and although there are several limitations to its similarity to the human condition, these can be overcome through detailed knowledge of its specific traits or with certain techniques. The rat has been used in many experimental protocols leading to bone loss, including hormonal interventions (ovariectomy, orchidectomy, hypophysectomy, parathyroidectomy), immobilization, and dietary manipulations. The aim of the current review is not only to present the ovariectomized rat and its advantages as an appropriate model for the research of osteoporosis, but also to provide information about the most relevant age and bone site selection according to the goals of each experimental protocol. In addition, several methods of bone mass evaluation are assessed, such as biochemical markers, densitometry, histomorphometry, and bone mechanical testing, that are used for monitoring and evaluation of this animal model in preventive or therapeutic strategies for osteoporosis.

Abstract: The material composition and structural design of bone determine its strength. Structure determines loads that can be tolerated but loads also determine structure. Bone modifies its material composition and structure to accommodate loads by adaptive modeling and remodeling. Adaptation is successful during growth but not aging because accumulating insults, including a reduction in the volume of bone formed in the basic multicellular unit (BMU), increased resorption in the BMU, increased remodeling rate in midlife in women and in some men because of sex hormone deficiency, and in both sexes in old age as a consequence of secondary hyperparathyroidism and reduced periosteal bone formation, all of which compromises the material composition of bone and its structure. An understanding of the mechanisms of adaptation and failed adaptation provides rational approaches to interventions that can prevent or restore bone fragility.

Abstract: Context: IL-1, IL-6, and TNF-α play an important role in the pathogenesis of osteoporosis in animals; however, evidence that these play a similar role in bone loss in human studies is limited. Objective: Our objective was to determine the associations between serum markers of inflammation and changes in bone mineral density (BMD) and urinary pyridinoline (PYR) to creatinine (Cr) ratio over 2.9 yr in older adults. Methods: A total of 168 randomly selected subjects (mean 63 yr, range 52–78, 48% female) was studied. BMD was measured by dual-energy x-ray absorptiometry at baseline (mean T score: −0.18 to −0.61) and 2.9 yr later. Serum high-sensitivity (hs) C-reactive protein (CRP), IL-6, TNF-α, and the urinary PYR/Cr ratio were measured on both occasions. Results: The mean annual loss of BMD was 0.15, 0.15, and 0.34% at total body, spine, and hip, respectively. Change in total body BMD was associated with baseline hs-CRP, IL-6, and TNF-α, as well as change in hs-CRP (β: −0.41%/U, 95% confidence interval −0.68...

Abstract: A 65-year-old asymptomatic man is concerned about his risk of osteoporosis. His mother died after a hip fracture at 74 years of age. The patient has no history of fractures but has lost 7.6 cm (3 in.) in height; he does not smoke and has never taken corticosteroids. He drinks two glasses of beer (16 oz, or about 0.5 liter, each) per day. His body-mass index (the weight in kilograms divided by the square of the height in meters) is 25. Measurements of bone mineral density with the use of dual-energy x-ray absorptiometry show T scores of-2.6 at the spine and -2.2 at the femoral neck, findings that are consistent with osteoporosis. What should you recommend?

Abstract: Context: Bariatric surgery is common and may be associated with deleterious effects on the skeleton. Objective: Our objective was to assess bone metabolism and bone mineral density (BMD) after Roux-en-Y gastric bypass. Design and Setting: We conducted a 1-yr prospective longitudinal study at a university hospital bariatric surgery practice and metabolic bone disease unit. Participants: Participants included 23 obese (mean body mass index 47 kg/m2) men and women, aged 20–64 yr. Main Outcome Measures: Serum PTH, 25-hydroxyvitamin D, osteocalcin, and urinary N-telopeptide, and BMD were assessed. Results: Patients lost 45 ± 2 kg 1 yr postoperatively (P < 0.01). PTH increased early (3 months, 43–50 pg/ml; P < 0.001) and urinary calcium dropped (161–92 mg/24 h; P < 0.01), despite doubling of calcium intake (1318–2488 mg/d; P < 0.001). Serum 25-hydroxyvitamin D concentrations were unchanged (23–26 ng/ml), although vitamin D intake increased by 260% (658 IU/d at baseline to 1698 IU/d at 12 months; P < 0.05). Mark...

Abstract: Bone morphogenetic proteins (BMPs) are known to induce ectopic bone. However, it is largely unknown how BMP signaling in osteoblasts directly regulates endogenous bone. This study investigated the mechanism by which BMP signaling through the type IA receptor (BMPR1A) regulates endogenous bone mass using an inducible Cre-loxP system. When BMPR1A in osteoblasts was conditionally disrupted during embryonic bone development, bone mass surprisingly was increased with upregulation of canonical Wnt signaling. Although levels of bone formation markers were modestly reduced, levels of resorption markers representing osteoclastogenesis were severely reduced, resulting in a net increase in bone mass. The reduction of osteoclastogenesis was primarily caused by Bmpr1a-deficiency in osteoblasts, at least through the RANKL-OPG pathway. Sclerostin (Sost) expression was downregulated by about 90% and SOST protein was undetectable in osteoblasts and osteocytes, whereas the Wnt signaling was upregulated. Treatment of Bmpr1a-deficient calvariae with sclerostin repressed the Wnt signaling and restored normal bone morphology. By gain of Smad-dependent BMPR1A signaling in mice, Sost expression was upregulated and osteoclastogenesis was increased. Finally, the Bmpr1a-deficient bone phenotype was rescued by enhancing BMPR1A signaling, with restoration of osteoclastogenesis. These findings demonstrate that BMPR1A signaling in osteoblasts restrain endogenous bone mass directly by upregulating osteoclastogenesis through the RANKL-OPG pathway, or indirectly by downregulating canonical Wnt signaling through sclerostin, a Wnt inhibitor and a bone mass mediator.

Abstract: The aim of the present clinical study was to determine the local bone density in dental implant recipient sites using computerized tomography (CT) and to investigate the influence of local bone density on implant stability parameters and implant success A total of 300 implants were placed in 111 patients between 2003 and 2005 The bone density in each implant recipient site was determined using CT Insertion torque and resonance frequency analysis were used as implant stability parameters The peak insertion torque values were recorded with OsseoCare machine The resonance frequency analysis measurements were performed with Osstell instrument immediately after implant placement, 6, and 12 months later Of 300 implants placed, 20 were lost, meaning a survival rate of % 933 after three years (average 37 ± 07 years) The mean bone density, insertion torque and RFA recordings of all 300 implants were 620 ± 251 HU, 361 ± 8 Ncm, and 657 ± 9 ISQ at implant placement respectively; which indicated statistically significant correlations between bone density and insertion torque values (p < 0001), bone density and ISQ values (p < 0001), and insertion torque and ISQ values (p < 0001) The mean bone density, insertion torque and RFA values were 645 ± 240 HU, 372 ± 7 Ncm, and 671 ± 7 ISQ for 280 successful implants at implant placement, while corresponding values were 267 ± 47 HU, 218 ± 4 Ncm, and 465 ± 4 ISQ for 20 failed implants; which indicated statistically significant differences for each parameter (p < 0001) CT is a useful tool to determine the bone density in the implant recipient sites, and the local bone density has a prevailing influence on primary implant stability, which is an important determinant for implant success

Abstract: The role of bone tissue's geometric distribution in hip fracture risk requires full evaluation in large population-based datasets. We tested whether section modulus, a geometric index of bending strength, predicted hip fracture better than BMD. Among 7474 women from the Study of Osteoporotic Fractures (SOF) with hip DXA scans at baseline, there were 635 incident hip fractures recorded over 13 yr. Hip structural analysis software was used to derive variables from the DXA scans at the narrow neck (NN), intertrochanter (IT), and shaft (S) regions. Associations of derived structural variables with hip fracture were assessed using Cox proportional hazard modeling. Hip fracture prediction was assessed using the C-index concordance statistic. Incident hip fracture cases had larger neck-shaft angles, larger subperiosteal and estimated endosteal diameters, greater distances from lateral cortical margin to center of mass (lateral distance), and higher estimated buckling ratios (p < 0.0001 for each). Areal BMD, cross-sectional area, cross-sectional moment of inertia, section modulus, estimated cortical thickness, and centroid position were all lower in hip fracture cases (p < 0.044). In hip fracture prediction using NN region parameters, estimated cortical thickness, areal BMD, and estimated buckling ratio were equivalent (C-index = 0.72; 95% CI, 0.70, 0.74), but section modulus performed less well (C-index = 0.61; 95% CI, 0.58, 0.63; p < 0.0001 for difference). In multivariable models combining hip structural analysis variables and age, effects of bone dimensions (i.e., lateral distance, subperiosteal diameter, and estimated endosteal width) were interchangeable, whereas age and neck-shaft angle were independent predictors. Several parsimonious multivariable models that were prognostically equivalent for the NN region were obtained combining a measure of width, a measure of mass, age, and neck-shaft angle (BMD is a ratio of mass to width in the NN region; C-index = 0.77; 95% CI, 0.75, 0.79). Trochanteric fractures were best predicted by analysis of the IT region. Because section modulus failed to predict hip fracture risk as well as areal BMD, the thinner cortices and wider bones among those who fractured may imply that simple failure in bending is not the usual event in fracture. Fracture might require initiation (e.g., by localized crushing or buckling of the lateral cortex).

Abstract: Bone sialoprotein (BSP) and osteopontin (OPN) are both highly expressed in bone, but their functional specificities are unknown. OPN knockout (−/−) mice do not lose bone in a model of hindlimb disuse (tail suspension), showing the importance of OPN in bone remodeling. We report that BSP−/− mice are viable and breed normally, but their weight and size are lower than wild-type (WT) mice. Bone is undermineralized in fetuses and young adults, but not in older (≥12 mo) BSP−/− mice. At 4 mo, BSP−/− mice display thinner cortical bones than WT, but greater trabecular bone volume with very low bone formation rate, which indicates reduced resorption, as confirmed by lower osteoclast surfaces. Although the frequency of total colonies and committed osteoblast colonies is the same, fewer mineralized colonies expressing decreased levels of osteoblast markers form in BSP−/− versus WT bone marrow stromal cultures. BSP−/− hematopoietic progenitors form fewer osteoclasts, but their resorptive activity on dentin is normal. Tail-suspended BSP−/− mice lose bone in hindlimbs, as expected. In conclusion, BSP deficiency impairs bone growth and mineralization, concomitant with dramatically reduced bone formation. It does not, however, prevent the bone loss resulting from loss of mechanical stimulation, a phenotype that is clearly different from OPN−/− mice.

Abstract: Measurement of bone mineral status may be a useful tool in identifying the children who could be exposed to an increased risk of osteoporosis in adulthood. Dual energy x-ray absorptiometry and peripheral quantitative computed tomography may be used to this purpose, but the exposure to ionizing radiation is a limiting factor for preventive studies in large populations of children. In the last years, quantitative ultrasound (QUS) methods have been developed to assess bone mineral status in some peripheral skeletal sites such as calcaneus, phalanges of the hand, and tibia. QUS techniques are safe, easy to use, radiation-free, and devices are portable, so that they are particularly indicated to assess bone mineral status in children. This review will concentrate on the main methodological principles of ultrasounds and the QUS variables derived from their application to bone tissue, technical differences and performance of QUS methods, factors influencing QUS measurements, normative data and results obtained in children with disturbances of growth or affected by disorders of bone and mineral metabolism, including the assessment of fracture risk, and comparison among QUS, dual energy x-ray absorptiometry, and peripheral quantitative computed tomography methods.

Abstract: OBJECTIVE To assess the effects of androgen deprivation therapy (ADT) on whole-body and regional muscle, fat and bone mass in men with prostate cancer without metastatic bone disease. PATIENTS AND METHODS Seventy-two men aged 44–88 years underwent spine, hip and whole-body dual-energy X-ray absorptiometry scans at baseline and after 36 weeks of ADT. The change in whole-body and regional lean mass (LM), fat mass (FM), and bone mineral content and density (BMD) were determined. In addition, the prostate specific antigen (PSA), serum testosterone and haemoglobin levels were measured, and the level of physical activity and fatigue assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-30. RESULTS The upper limb, lower limb, trunk and whole-body LM decreased by a mean (sem) of 5.6 (0.6)%, 3.7 (0.5)%, 1.4 (0.5)% and 2.4 (0.4)% (P < 0.01), respectively, while FM increased by 20.7 (3.3)%, 18.7 (2.7)%, 12.0 (2.5)% and 13.8 (2.3)% (P < 0.001). Hip, spine, whole-body and upper limb BMD decreased by 1.5 (0.5)%, 3.9 (0.4)%, 2.4 (0.3)% and 1.3 (0.3%) (P < 0.001), but not lower limb BMD. Serum testosterone, PSA and haemoglobin levels decreased by 93.3 (0.4)%, 98.2 (0.5)%, and 8.8 (0.9)% (P < 0.001), respectively. In addition, physical activity levels decreased and levels of fatigue increased. CONCLUSION After 36 weeks of ADT there was a significant decrease in whole-body and regional LM and bone mass, while whole-body and regional FM increased in older men with prostate cancer. Strategies to counteract changes in soft tissue and bone mass during ADT should be formulated to minimize the risk of sarcopenia, osteoporosis and obesity.

Abstract: Context: Although type 2 diabetic patients are at increased risk of fractures, bone mineral density (BMD) may not be useful for assessing the risk. Recent studies have reported that increased bone content of pentosidine (PEN) is associated with its plasma concentration and bone fragility. Objective and Methods: To examine the association between serum PEN levels and vertebral fractures (VFs) in Japanese type 2 diabetic patients (77 males older than 50 yr and 76 postmenopausal females), we compared parameters including BMD, PEN, serum bone-specific alkaline phosphatase, and urinary levels of N-telopeptide between those with and without VFs. Results: Comparison of diabetic subjects with and without VFs revealed no significant differences in BMD values or bone metabolic markers in either gender. In contrast, PEN levels in women with VFs were significantly higher than in those without VFs (0.0440 ± 0.0136 vs. 0.0321 ± 0.0118 μg/ml; P < 0.001). Multivariate logistic regression analysis adjusted for age, height...

Abstract: Background Data on the influence of gonadal hormones on incident fracture risk in elderly men are limited. We prospectively examined the relationship between serum levels of testosterone and estradiol and future fracture risk in community-dwelling men. Methods A total of 609 men older than 60 years had been observed between January 1989 and December 2005, with the median duration being 5.8 years (up to 13 years). Clinical risk factors, including bone mineral density and lifestyle factors, were assessed at baseline. Serum testosterone and estradiol levels were measured by tandem mass spectrometry. The incidence of a low-trauma fracture was ascertained during follow-up. Results During follow-up, 113 men had at least 1 low-trauma fracture. The risk of fracture was significantly increased in men with reduced testosterone levels (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.09-1.62). After adjustment for sex hormone–binding globulin, serum testosterone (HR, 1.48; 95% CI, 1.22-1.78) and serum estradiol (HR, 1.21; 95% CI, 1.00-1.47) levels were associated with overall fracture risk. After further adjustment for major risk factors of fractures (age, weight or bone mineral density, fracture history, smoking status, calcium intake, and sex hormone–binding globulin), lower testosterone was still associated with increased risk of fracture, particularly with hip (HR, 1.88; 95% CI, 1.24-2.82) and nonvertebral (HR, 1.32; 95% CI, 1.03-1.68) fractures. Conclusion In community-dwelling men older than 60 years, serum testosterone is independently associated with the risk of osteoporotic fracture and its measurement may provide additional clinical information for the assessment of fracture risk in elderly men.

Abstract: Osteoporosis, a highly heritable disease, is characterized mainly by low bone-mineral density (BMD), poor bone geometry, and/or osteoporotic fractures (OF). Copy-number variation (CNV) has been shown to be associated with complex human diseases. The contribution of CNV to osteoporosis has not been determined yet. We conducted case-control genome-wide CNV analyses, using the Affymetrix 500K Array Set, in 700 elderly Chinese individuals comprising 350 cases with homogeneous hip OF and 350 matched controls. We constructed a genomic map containing 727 CNV regions in Chinese individuals. We found that CNV 4q13.2 was strongly associated with OF (p = 2.0 × 10−4, Bonferroni-corrected p = 0.02, odds ratio = 1.73). Validation experiments using PCR and electrophoresis, as well as real-time PCR, further identified a deletion variant of UGT2B17 in CNV 4q13.2. Importantly, the association between CNV of UGT2B17 and OF was successfully replicated in an independent Chinese sample containing 399 cases with hip OF and 400 controls. We further examined this CNV's relevance to major risk factors for OF (i.e., hip BMD and femoral-neck bone geometry) in both Chinese (689 subjects) and white (1000 subjects) samples and found consistently significant results (p = 5.0 × 10−4 −0.021). Because UGT2B17 encodes an enzyme catabolizing steroid hormones, we measured the concentrations of serum testosterone and estradiol for 236 young Chinese males and assessed their UGT2B17 copy number. Subjects without UGT2B17 had significantly higher concentrations of testosterone and estradiol. Our findings suggest the important contribution of CNV of UGT2B17 to the pathogenesis of osteoporosis.

Abstract: The aim of this study was to evaluate the total antioxidant status (TAS), total oxidative status (TOS) and oxidative stress index (OSI) in patients with postmenopausal osteoporosis. We also investigate the relation between bone mineral density and oxidative/antioxidative parameters. Thirty-nine patients with osteoporosis and 26 healthy controls were included in the study. Plasma TAS, TOS levels were determined by using a novel automated methods. Plasma TOS and OSI value were significantly higher, and plasma TAS level was lower in patients than in healthy controls (P < 0.001 for all). There was a significant negative correlation between OSI and BMD in lumbar and femoral neck region (r = -0.63, P < 0.001; r = 0.40, P = 0.018). The results of this study indicated that increased osteoclastic activity and decreased osteoblastic activity may be associated with an imbalance between oxidant and antioxidant status in postmenopausal osteoporosis. Therefore, supplementation of antioxidant-enriched diet to the therapy might shed light on the development of novel therapeutic strategies for osteoporosis.