Lumbar Vertebral Trabecular Bone Research Articles

Once-Weekly Teriparatide Treatment Prevents Microdamage Accumulation in the Lumbar Vertebral Trabecular Bone of Ovariectomized Cynomolgus Monkeys

The effect of teriparatide treatment on microdamage accumulation has yet to be examined in animal studies. The purpose of this study was to investigate the effect of once-weekly teriparatide treatment on bone microdamage accumulation and the relationship between microdamage parameters and bone mass, architecture, turnover, and collagen cross-linking in the lumbar vertebral trabecular bone of ovariectomized (OVX) cynomolgus monkeys. Female monkeys were divided into four groups (n = 18–20 per group): (1) SHAM group, (2) OVX group, (3) OVX with 1.2 µg/kg once-weekly teriparatide group (LOW group), (4) OVX with 6.0 µg/kg once-weekly teriparatide group (HIGH group). After 18 months, all animals were double-labeled with calcein for histomorphometry. L3 and L7 lumbar vertebrae were harvested and analyzed for differences in histomorphometry, microdamage, and collagen cross-linking. The iliac crest was also analyzed for differences in bone turnover. In the OVX group, cancellous bone mass was reduced and microdamage accumulation was increased as compared with the SHAM control. Once-weekly teriparatide at both doses prevented the decrease in bone mass and increase in microdamage accumulation, and improved the distribution of collagen cross-linkage types. Regression analyses indicated that decreased microdamage accumulation was associated with reduced non-enzymatic cross-link pentosidine rather than increased cancellous bone mass or enzymatic cross-links. These findings suggest that once-weekly teriparatide treatment decreases microdamage accumulation by recovering the balance in collagen cross-links.

Dependence of anisotropy of human lumbar vertebral trabecular bone on quantitative computed tomography-based apparent density.

Most studies investigating human lumbar vertebral trabecular bone (HVTB) mechanical property-density relationships have presented results for the superior-inferior (SI), or "on-axis" direction. Equivalent, directly measured data from mechanical testing in the transverse (TR) direction are sparse and quantitative computed tomography (QCT) density-dependent variations in the anisotropy ratio of HVTB have not been adequately studied. The current study aimed to investigate the dependence of HVTB mechanical anisotropy ratio on QCT density by quantifying the empirical relationships between QCT-based apparent density of HVTB and its apparent compressive mechanical properties--elastic modulus (E(app)), yield strength (σ(y)), and yield strain (ε(y))--in the SI and TR directions for future clinical QCT-based continuum finite element modeling of HVTB. A total of 51 cylindrical cores (33 axial and 18 transverse) were extracted from four L1 human lumbar cadaveric vertebrae. Intact vertebrae were scanned in a clinical resolution computed tomography (CT) scanner prior to specimen extraction to obtain QCT density, ρ(CT). Additionally, physically measured apparent density, computed as ash weight over wet, bulk volume, ρ(app), showed significant correlation with ρ(CT) [ρ(CT) = 1.0568 × ρ(app), r = 0.86]. Specimens were compression tested at room temperature using the Zetos bone loading and bioreactor system. Apparent elastic modulus (E(app)) and yield strength (σ(y)) were linearly related to the ρ(CT) in the axial direction [E(SI) = 1493.8 × (ρ(CT)), r = 0.77, p < 0.01; σ(Y,SI) = 6.9 × (ρ(CT)) − 0.13, r = 0.76, p < 0.01] while a power-law relation provided the best fit in the transverse direction [E(TR) = 3349.1 × (ρ(CT))(1.94), r = 0.89, p < 0.01; σ(Y,TR) = 18.81 × (ρ(CT))(1.83), r = 0.83, p < 0.01]. No significant correlation was found between ε(y) and ρ(CT) in either direction. E(app) and σ(y) in the axial direction were larger compared to the transverse direction by a factor of 3.2 and 2.3, respectively, on average. Furthermore, the degree of anisotropy decreased with increasing density. Comparatively, ε(y) exhibited only a mild, but statistically significant anisotropy: transverse strains were larger than those in the axial direction by 30%, on average. Ability to map apparent mechanical properties in the transverse direction, in addition to the axial direction, from CT-based densitometric measures allows incorporation of transverse properties in finite element models based on clinical CT data, partially offsetting the inability of continuum models to accurately represent trabecular architectural variations.

Hepatic lipase is expressed by osteoblasts and modulates bone remodeling in obesity

A number of unexpected molecules were recently identified as products of osteoblasts, linking bone homeostasis to systemic energy metabolism. Here we identify the lipolytic enzyme hepatic lipase (HL, encoded by Lipc) as a novel cell-autonomous regulator of osteoblast function. In an unbiased genome-wide expression analysis, we find Lipc to be highly induced upon osteoblast differentiation, verified by quantitative Taqman analyses of primary osteoblasts in vitro and of bone samples in vivo. Functionally, loss of HL in vitro leads to increased expression and secretion of osteoprotegerin (OPG), while expression of some osteoblast differentiation makers is impaired. When challenging energy metabolism in a diet-induced obesity (DIO) study, lack of HL leads to a significant increase in bone formation markers and a decrease in bone resorption markers. Accordingly, in the DIO setting, we observe in Lipc−/− animals but not in wild-type controls a significant increase in lumbar vertebral trabecular bone mass and formation rate as well as in femoral trabecular bone mass and cortical thickness. Taken together, we demonstrate that HL expressed by osteoblasts has an impact on osteoblast OPG expression and that lack of HL leads to increased bone mass in DIO. These data provide a novel and completely unexpected molecular link in the complex interplay of osteoblasts and systemic energy metabolism.

Short-term activation of liver X receptors inhibits osteoblasts but long-term activation does not have an impact on murine bone in vivo

Liver X receptors (LXRs) are nuclear receptors that play a crucial role in the transcriptional control of lipid metabolism. Pharmacological LXR activation is an attractive concept for the treatment of atherosclerosis. Genetic LXR deficiency in mice has been shown to have an effect on bone turnover and structure and LXR activation is known to influence the osteogenic differentiation of bone marrow stromal cells. Therefore, therapeutic pharmacological LXR activation may have relevant effects on bone. Here, using two synthetic LXR ligands, T0901317 and GW3965, we investigated the effect of LXR activation on murine osteoblasts and the influence of long-term LXR activation on bone in vivo in mice. Short term (48 h) in vitro treatment of primary murine osteoblasts with T0901317 resulted in a dose-dependent decrease of osteocalcin and alkaline phosphatase mRNA and protein. In vivo, a 6-day treatment of C57BL/6 J mice with T0901317 led to a 40% reduction of serum osteocalcin concentrations. Long-term (12-week) oral administration of T0901317 or GW3965 influenced the expression of established LXR target genes in liver and intestine, but did not alter trabecular and cortical bone structure or bone turnover as determined by total skeleton radiography, histomorphometric analysis of lumbar vertebral trabecular bone, micro CT analysis of femur cortical bone and biochemical determination of bone formation and resorption markers. We conclude that short-term pharmacological LXR activation has the potential to profoundly influence osteoblast function, but that long-term LXR activation in vivo has no adverse effects on the murine skeleton.

Age- and direction-related adaptations of lumbar vertebral trabecular bone with respect to apparent stiffness and tissue level stress distribution

The objective of this study was to study the age-related adaptation of lumbar vertebral trabecular bone at the apparent level, as well as the tissue level in three orthogonal directions. Ninety trabecular specimens were obtained from six normal L4 vertebral bodies of six male cadavers in two age groups, three aged 62 years and three aged 69 years, and were scanned using a high-resolution micro-computed tomography (micro-CT) system, then converted to micro-finite element models to do micro-finite element analyses. The relationship between apparent stiffness and bone volume fraction, and the tissue level von Mises stress distribution for each trabecular specimen when compressed separately in the longitudinal direction, medial–lateral and anterior–posterior directions (transverse directions) were derived and compared between two age groups. The results showed that at the apparent level, trabecular bones from 69-year group had stiffer bone structure relative to their volume fractions in all three directions, and in both age groups, changes in bone volume fraction could explain more variations in apparent stiffness in the longitudinal direction than the transverse directions; at the tissue level, aging had little effect on the tissue von Mises stress distributions for the compressions in all the three directions. The novelty of the present study was that it provided quantitative assessments on the age and direction-related adaptation of Chinese male lumbar vertebral trabecular bone from two different levels: stiffness at the apparent level and stress distribution at the tissue level. It may help to understand the failure mechanisms and fracture risks of vertebral body associated with aging and direction for the prevention of fracture risks in elder individuals.

Lasofoxifene (CP-336,156), a novel selective estrogen receptor modulator, in preclinical studies

Estrogen replacement therapy is reported to reduce the incidence of vertebral fractures in postmenopausal women, however, its compliance is limited because of side effects and safety concerns. Estrogen's side effects on breast and uterine tissues leading to the potential increased risk of uterine and breast cancer limit widespread estrogen usage. Thus, there is a significant medical need for a therapy that protects against postmenopausal bone loss but is free of estrogen's negative effects on reproductive tissues. Selective estrogen receptor modulators (SERMs) have been investigated as an alternative to hormone replacement therapy. One such compound, raloxifene, has been approved for the prevention and treatment of osteoporosis. Lasofoxifene (LAS), a new, nonsteroidal, and potent SERM, is an estrogen antagonist or agonist depending on the target tissue. LAS selectively binds with high affinity to human estrogen receptors. In ovariectomized (OVX) rat studies, LAS prevented the decrease in femoral bone mineral density, tibial and lumbar vertebral trabecular bone mass at an ED100 of about 60 μg/kg/day. LAS inhibited the activation of trabecular and endocortical bone resorption and bone turnover in tibial metaphyses and diaphyses, and lumbar vertebral body in OVX rats. In addition, LAS decreased total serum cholesterol, inhibited body weight gain and increased soleus muscle weight in OVX rats. Similarly, LAS prevented bone loss induced by orchidectomy or aging in male rats by decreasing bone resorption and bone turnover while it had no effect in the prostate. Further, LAS decreased total serum cholesterol in intact aged male rats or in orchidectomized male rats. Synergestic skeletal effects were found with LAS in combination with bone anabolic agents such as prostaglandin E2 (PGE2), parathyroid hormone (PTH) or a growth hormone secretagoue (GHS) in OVX rats. In combination with estrogen, LAS inhibited the uterine stimulating effects of estrogen but did not block the bone protective effects of estrogen. In immature and aged female rats, LAS did not affect the uterine weight and uterine histology. In OVX adult female rats, LAS slightly but significantly increased uterine weight. These results demonstrated that LAS produced effects on the skeleton indistinguishable from estrogen in female and male rats. However, unlike estrogen, LAS had little effect on uterine weight and cellular proliferation of uterus in female rats. In preclinical anti-tumor studies, LAS inhibited human breast cancer growth in mice bearing MCF7 tumors, prevented NMU-induced mammary carcinomas and possessed chemotherapeutic effects in NMU-induced carcinomas in rats. Therefore, we conclude that LAS possesses the antiestrogenic effects in breast tissue and estrogenic effects in bone and serum cholesterol, but lacks estrogen's side effects on uterine tissue. These data support the therapeutic potential of LAS for the prevention and treatment of postmenopausal bone loss and mammary carcinomas in humans.

Effects of Corticosteroids on Mechanical Strength of Intervertebral Joints and Vertebrae in Dogs

Dogs with hyperadrenocorticism had a higher incidence of intervertebral joint disease, i.e., disc protrusion or spondylosis. In comparing cases of hyperadrenocorticism with age- and breed-matched controls with hypothyroidism, the incidence was significantly greater than expected. This was not seen, however, in beagle dogs in which the incidence was already high and attributed to chondrodystrophoid tendencies in this breed. To investigate the pathogenesis of this association and its possible relationship to steroid-induced osteopenia, adult dogs were given a placebo, prednisone, or prednisone plus calcium for six months. Torque testing of intervertebral joints revealed a consistent trend of lower force to failure in both prednisone-treated groups, but the difference was not statistically significant. In these dogs with mild to moderate hyperadrenocorticism, compression tests of intact vertebral bodies were not significantly different, but blocks of trabecular bone cut from the vertebral bodies failed at significantly lower compressive forces in both prednisone-treated groups compared with controls. Histomorphometric evaluation of lumbar vertebral trabecular bone revealed that the percentage of bone volume was not significantly decreased in the prednisone-treated groups. Nor was there any difference in the thickness or porosity of vertebral end-plates, which might contribute to weakening of intervertebral ligamentous insertions.

Trabecular bone remodeling and bone mineral density in the adult cat during chronic dietary acidification with ammonium chloride

Ammonium chloride (NH4Cl) is used as a urinary acidifier in the treatment and prevention of feline urologic syndrome. It is reported to cause alterations in calcium and bone metabolism in humans, dogs, and rats. Adult cats with normal renal function were fed 1.5% NH4Cl for 6 months to study the effects of chronic dietary acidification on trabecular bone remodeling of the iliac crest and bone mineral density (BMD) of lumbar vertebral trabecular bone and femoral cortex. Histomorphometric analyses of iliac crest biopsies were performed before and after treatment. Static and dynamic parameters of bone resorption and formation were determined. Single-energy quantitative computed tomography (SEQCT) was used to measure lumbar trabecular and femoral cortical BMD. There were no significant treatment effects in iliac crest trabecular bone remodeling or BMD of the vertebrae and femora. Bone remodeling activity decreased with time in both acidotic and control cats. Vertebral BMD increased with time in both groups of cats, whereas no change was seen in the femora. Thus, chronic dietary acidification for 6 months with therapeutic levels of NH4Cl produced no significant changes in trabecular bone remodeling or bone mineral density in adult cats.

Quantitative computed tomography reflects vertebral fracture morbidity in osteopenic patients.

We studied the relationship between spontaneous vertebral compression fractures and lumbar vertebral trabecular bone density in 69 consecutive patients with suspected osteopenia. Seven had biopsy-confirmed osteomalacia. The remaining 62 were divided into three groups: group 1--asymptomatic patients suspected of having osteopenia on plain films, but with no vertebral compression fractures (N = 24); group II--those with one to five vertebral compression fractures (N = 16); and group III--those with six or more vertebral compression fractures (N = 22). A quantitative computed tomographic (QCT) scan of the lumbar spine was performed on all patients. Patients in group I had QCT values of 94 +/- 23 mg/cm3 (mean +/- SE); those in group II had QCT values of 66 +/- 28 mg/cm3; and those in group III had values of 34 +/- 28 mg/cm3. There were significant differences among all groups (P less than .001), although there was considerable overlap of individuals among the groups. There was no significant difference between the mean QCT value of patients with one compression fracture and the value of those with between two and five compression fractures. Patients with biopsy-proven osteomalacia had higher vertebral trabecular bone density than patients with osteoporosis and compression fractures. Our study provides evidence suggesting a strong inverse relationship between QCT-measured vertebral bone density and the presence of vertebral compression fractures in a group of osteopenic patients.

A study of the compressive properties of lumbar vertebral trabeculae: effects of tissue characteristics.

The compressive material properties of human lumbar vertebral trabecular bone were examined and compared to in vivo and in vitro measures of bone density and to the degree of macroscopic disc degeneration. No significant differences in the material properties were found for segment level (L1-L4) or for degeneration grade (I-IV), although trabecular bone specimens from segments with slightly degenerated disks (I-II) were stronger (24%) and stiffer (16%) on the average than specimens from segments with severely degenerated discs. Significant positive logarithmic regressions were obtained, however, between the in vivo and in vitro measures of trabecular bone density and trabecular bone mechanical properties. The results indicate that in vivo mineral measurements can accurately estimate the compressive material properties of lumbar vertebral trabeculae.

The Relation of Running to Bone and Joint Disease

To the Editor.— Lane et al 1 have demonstrated a higher mineral content of lumbar vertebral trabecular bone in runners. Their data, however, should be interpreted with caution until the smoking habits of their control subjects are known. Cigarette smoking is well established as a risk factor for the development of osteoporosis. 2-6 Since habitual runners are almost exclusively nonsmokers, any satisfactory control population should demonstrate comparable tobacco abstinence.