The skeletal muscle cross sectional area in long-term bisphosphonate users is smaller than that of bone mineral density-matched controls with increased serum pentosidine concentrations.

Bisphosphonates are effective in increasing bone mineral density (BMD), but fragility fractures can still occur despite bisphosphonate treatment. The purpose of this study was to determine if long-term bisphosphonate users have characteristic findings in the musculoskeletal system, which could put them at risk of developing typical or atypical femoral fractures. We recruited 40 female patients who had taken bisphosphonates for more than 3 years. The control group included 60 volunteers who were matched by age, body mass index, and dual-energy X-ray absorptiometry-derived BMDs. We measured the skeletal muscle cross sectional area around the proximal thigh and buckling ratio of the femoral neck using quantitative computed tomography (qCT) and several biochemical markers of bone metabolism. Those parameters were compared between the groups. While no significant differences of buckling ratio derived from qCT were detected, the skeletal muscle cross sectional area was significantly smaller in the long-term bisphosphonate users than in the controls. Furthermore, the serum pentosidine level was significantly higher in the bisphosphonate users than in the controls. To determine if those differences were attributable to bisphosphonate treatment, we further compared those parameters between before and after 3 years of bisphosphonate treatment in 32 patients. After 3 years of bisphosphonate treatment, the BMD of the femoral neck and serum pentosidine level increased but not the skeletal muscle cross sectional area. In the present study, the skeletal muscle mass did not match the bone mass in long-term bisphosphonate users, thus suggesting that increases in BMD by bisphosphonates are unlikely to have secondary positive effects on the surrounding skeletal muscles. Also, serum pentosidine levels were greater in the long-term bisphosphonate users. Further study is necessary to test if such patients are prone to develop typical or atypical femoral fractures.

Factors that characterize bone health with aging in healthy postmenopausal women.

The exponential increase in the incidence of fragility fractures in older people is attributed to attenuation of both bone strength and neuromuscular function. Decrease in bone mineral density (BMD) does not entirely explain this increase. The objective of this study is to investigate the effect of age on various parameters related to bone health with aging, and to identify combinations of factors that collectively express the bone metabolic state in healthy postmenopausal women. Height, weight, and grip strength were measured in 135 healthy postmenopausal volunteer women. Hip BMD, biomechanical indices derived from quantitative computed tomography (QCT), cross-sectional areas of muscle and fat of the proximal thigh, and various biochemical markers of bone metabolism were measured. A smaller group of factors explanatory for bone health was identified using factor analysis and each was newly named. As a result, the factors bone mass, bone turnover, bone structure, and muscle strength had the greatest explanatory power for assessing the bone health of healthy postmenopausal women. Whereas dual X-ray absorptiometry parameters only loaded on the factor bone mass, QCT parameters loaded on both the factors bone mass and bone structure. Most bone turnover markers loaded on the factor bone turnover, but deoxypyridinoline loaded on both bone turnover and muscle strength. Age was negatively correlated with bone mass (r = -0.49, p < 0.001) and muscle strength (r = -0.67, p < 0.001). We conclude that aging is associated as much with muscle weakening as with low BMD. More attention should be paid to the effects of muscle weakening during aging in assessments of bone health.

[Assessment of volumetric bone mineral density and geometry for hip with clinical CT device].

It is one of the most important challenges for preventing hip fractures to establish an accurate non-invasive assessment of hip fracture risk. Quantitative computed tomography (QCT) is able to analyze not only volumetric bone mineral density (mg/cm3) of trabecular and cortical bone compartment separately, but also geometry and biomechanical parameters in bone such as cross-sectional area, cortical bone thickness, section modulus, buckling ratio etc. The analysis of geometry and biomechanical parameters at hip could provide better prediction of hip fracture risk, better understanding pathogenesis of hip fractures, and thus better selection of drug and/or lifestyle-based interventions.

A novel underuse model shows that inactivity but not ovariectomy determines the deteriorated material properties and geometry of cortical bone in the tibia of adult rats.

Our goal in this study was to determine to what extent the physiologic consequences of ovariectomy (OVX) in bones are exacerbated by a lack of daily activity such as walking. We forced 14-week-old female rats to be inactive for 15 weeks with a unique experimental system that prevents standing and walking while allowing other movements. Tibiae, femora, and 4th lumbar vertebrae were analyzed by peripheral quantitative computed tomography (pQCT), microfocused X-ray computed tomography (micro-CT), histology, histomorphometry, Raman spectroscopy, and the three-point bending test. Contrary to our expectation, the exacerbation was very much limited to the cancellous bone parameters. Parameters of femur and tibia cortical bone were affected by the forced inactivity but not by OVX: (1) cross-sectional moment of inertia was significantly smaller in Sham-Inactive rat bones than that of their walking counterparts; (2) the number of sclerostin-positive osteocytes per unit cross-sectional area was larger in Sham-Inactive rat bones than in Sham-Walking rat bones; and (3) material properties such as ultimate stress of inactive rat tibia was lower than that of their walking counterparts. Of note, the additive effect of inactivity and OVX was seen only in a few parameters, such as the cancellous bone mineral density of the lumbar vertebrae and the structural parameters of cancellous bone in the lumbar vertebrae/tibiae. It is concluded that the lack of daily activity is detrimental to the strength and quality of cortical bone in the femur and tibia of rats, while lack of estrogen is not. Our inactive rat model, with the older rats, will aid the study of postmenopausal osteoporosis, the etiology of which may be both hormonal and mechanical.

Regional distinctions in cortical bone mineral density measured by pQCT can predict alterations in material property at the tibial diaphysis of the Cynomolgus monkey.

We examined whether regional differences in cortical bone mineral density (Ct.BMD) measured by peripheral quantitative computed tomography is related to the heterogeneity of bone tissue and whether regional Ct.BMD is a better indicator of changes in bone material properties. Bilateral tibiae were obtained from 17 female adult Cynomolgus monkeys (Macaca fascicularis; mean age 16.8 years). After determining that Ct.BMD was similar between the right and left tibiae, the left tibiae were used for bone histomorphometry and the right for a three-point bending test. The Ct.BMD in the posterior quadrant was significantly higher than that in the anterior quadrant. In the bone histomorphometric analysis, all parameters (i.e., average osteonal area, average osteonal bone area, osteon population density, percent osteonal area [%On.Ar], percent osteonal bone area [%On.B.Ar], percent osteonal area of initial remodeling [%Il.On.Ar], percent osteonal area of secondary remodeling [%Sd.On.Ar], porosity, and percent osteoid area in the posterior region) were significantly lower than those in the anterior region. The results indicated that in the same cross-section, bone tissue structure was heterogeneous. Both total- and posterior-Ct.BMD were positively correlated with breaking stress and negatively correlated with toughness, whereas anterior-Ct.BMD was positively correlated with elastic modulus. Backward stepwise multiple regression analyses indicated that posterior-Ct.BMD and total-Ct.BMD were the best variables for predicting breaking stress and toughness, respectively, when age is taken into account. The %On.Ar, %On.B.Ar, and %Il.On.Ar in the posterior region were negatively correlated with elastic modulus. The %On.Ar, %On.B.Ar, and %Sd.On.Ar in the posterior region were positively correlated with toughness. These findings indicated that regional Ct.BMD measurement is useful to assess changes in the material properties of bone associated with the degree of mineralization. In particular, anterior-, posterior-, and total-Ct.BMD can be used separately to predict changes in the material properties of the tibial diaphysis.

Correlations between periodontitis and loss of mandibular bone in relation to systemic bone changes in postmenopausal Japanese women.

A new method of measuring mandibular alveolar bone mineral density (BMD) was applied to 40 postmenopausal Japanese women aged 50-69 years exhibiting minimal to mild periodontal diseases. Lumbar spine BMD was measured by dual X-ray absorptiometry (DXA) and calcaneus speed of sound (SOS) by quantitative ultrasound (QUS). There were age-related decreases of alveolar BMD, calcaneus SOS and vertebral BMD. There were significant correlations between two of the respective bone mass values. Correlations between clinical dental findings and bone mass data including alveolar BMD, SOS and lumbar spine BMD were investigated. Significant correlations were demonstrated between alveolar BMD and calcaneus SOS or vertebral BMD. Alveolar BMD showed significant correlation with clinical dental findings including periodontal pocket depth and mobility as well as calcaneus SOS and lumbar spine BMD. Using multivariate analysis combinations of univariate predictors, including deoxypyridinoline (DPD), significantly predicted attachment levels. The SOS value was useful combined with other predictors for predicting attachment level. It was concluded that the new method of evaluating alveolar BMD is useful to predict systemic bone mass and strength as well as dental clinical findings.

Subcutaneous injections of a TNF-alpha antagonistic peptide inhibit both inflammation and bone resorption in collagen-induced murine arthritis.

The cyclic peptide WP9QY (YCWSQYLCY), which was designed to mimic the most critical tumor necrosis factor (TNF) alpha recognition loop on type1 TNF receptor, antagonizes the effects of TNFalpha. In this study, we investigated the effects of WP9QY peptide on collagen-induced arthritis (CIA) mice to evaluate its effects on inflammatory bone destruction. DBA/1J mice were injected intradermally at the base of the tail with bovine type II collagen, emulsified in complete Freund's adjuvant on day 0 and 21. The three sets of WP9QY peptide injections (24 mg/kg x 8 times per day) were performed before the onset of paw swelling. Mice were sacrificed at day 38 and thereafter, the arthritis scores as well as radiographical and histological outcomes were assessed. WP9QY peptide inhibited CIA-induced increase in the arthritis score. Furthermore, histomorphometric analysis of the tibial epiphysis region revealed that WP9QY peptide inhibited the increase of synovial pannus infiltration and the decrease of bone volume, which were induced by the CIA. The WP9QY treatment prevented the inflammation as well as bone destruction of the joints in the CIA mice, suggesting that the administration of WP9QY peptide might be useful for developing a drug to prevent inflammatory bone destruction.

Human parathyroid hormone (1-34) accelerates the fracture healing process of woven to lamellar bone replacement and new cortical shell formation in rat femora.

This study aimed to test whether intermittent treatment of human parathyroid hormone [hPTH(1-34)] disturbs or accelerates the fracture healing process using rat surgical osteotomy model. One hundred five, 5-week-old SD rats were allocated to vehicle control (CNT) and four PTH groups; 10 and 30 microg/kg of hPTH(1-34) treatment before surgery (P10, P30), and treatment before and after surgery (C10, C30). All animals were given subcutaneous injections three times a week for 3 weeks. Then, fractures were produced by transversely cutting the midshaft of bilateral femora and fixing with intramedullary wire. Human PTH(1-34) treatment was continued in C10 and C30 groups until sacrifice at 3, 6, and 12 weeks after surgery. The femora were assessed by peripheral quantitative computed tomography, three-point bending mechanical test, and histomorphometry. Total cross-sectional area was not significantly different among all groups at any time point. At 3 weeks after surgery, the lamellar bone/callus area was significantly increased in C10 and C30 groups compared to the other groups. At 6 weeks, remodeling of woven bone to lamellar bone in the callus was almost complete in all groups. At 12 weeks, percent new cortical shell area was significantly higher in C10 and C30 groups compared to the other groups, and the ultimate load in mechanical testing was significantly higher in C30 group than in CNT, P10, and P30 groups. Intermittent PTH treatment at 30 microg/kg before and after osteotomy accelerated the healing process as evidenced by earlier replacement of woven bone to lamellar bone, increased new cortical shell formation, and increased the ultimate load up to 12 weeks after osteotomy.

Suppressed bone turnover by long-term bisphosphonate treatment accumulates microdamage but maintains intrinsic material properties in cortical bone of dog rib.

UNLABELLED: Effects of long-term suppression of bone remodeling by bisphosphonate were investigated in cortical bone of dog rib. Although microdamage was accumulated, BMD was increased without increasing cortical bone area. Consequently, the intrinsic material properties were not reduced. INTRODUCTION: Recently, we have reported that long-term suppression of bone remodeling increases microdamage accumulation but is not necessarily associated with vertebral fragility because of compensated increase of bone mass and improved microarchitecture. This study aimed to investigate the effect of long-term suppression of bone remodeling by bisphosphonate on the degree of mineralization, accumulation of microdamage, and mechanical properties of cortical bone in the same dogs. MATERIALS AND METHODS: Twenty-nine 1-year-old beagles (15 males, 14 females) were divided into three groups and treated daily with vehicle (CNT) or with incadronate at a dose of 0.3 (LOW) or 0.6 mg/kg/day (HIGH) orally for 3 years. After death, pQCT, histomorphometry, microdamage measurements, and three-point bending mechanical test were performed using the ninth rib. RESULTS: Cortical BMD was increased in the incadronate-treated groups. Cortical activation frequency was suppressed by 82% and 70% in HIGH and LOW, respectively, compared with CNT, without impairment of mineralization. Microdamage accumulation was increased in both incadronate-treated groups. Although there were no significant differences in total and cortical area among the three groups, structural mechanical properties were significantly increased after incadronate treatment while intrinsic material properties were not changed in the incadronate-treated groups. CONCLUSION: This study suggests that long-term suppression of bone remodeling by bisphosphonate increases microdamage accumulation. However, this was not necessarily associated with a reduction of intrinsic material properties probably because of an increased degree of mineralization.