A Structural Approach to Renal Bone Disease

Beginning with the report in 1994 that an adult male with homozygous loss of estrogen receptor α (ERα) had unfused epiphyses and osteopenia,(1) there is now considerable evidence from observational and interventional studies (summarized in Khosla and colleagues(2)) that estrogen is the dominant regulator of bone metabolism in men. Indeed, a legitimate argument can be made that testosterone is largely a prohormone for the skeleton, with its effects on bone mediated principally via aromatization to estrogen, although it remains likely that testosterone contributes to bone size via effects on periosteal apposition and perhaps indirectly to bone mass by increasing muscle mass.

Parathyroid hormone (PTH) may be anabolic at trabecular bone and catabolic in cortical bone. As many regions of the skeleton contain both types of bone, the effects of PTH deficiency or excess may be difficult to evaluate using bone densitometry, a technique that integrates the cortical and trabecular compartments of bone. We asked the following questions: 1) Is the higher bone mineral density (BMD) in postsurgical hypoparathyroidism due to higher cortical, not trabecular, bone? 2) Is age-related bone loss slowed in patients with postsurgical hypoparathyroidism? 3) Is lower BMD in primary hyperparathyroidism the result of deficits in cortical, not trabecular, bone? BMD of the lumbar spine, proximal femur, distal radius, and femoral midshaft was measured by postero-anterior (PA) scanning, while bone mineral content (BMC) of the third lumbar vertebra was measured by lateral scanning using dual x-ray absorptiometry in 10 women, ages 64.6 +/- 3.2 yr, with postsurgical hypoparathyroidism and in 25 women, ages 68.7 +/- 1.6 yr, with primary hyperparathyroidism. Measurements were repeated 4.7 +/- 0.6 yr later in 8 patients with hypoparathyroidism and 4.0 +/- 0.4 yr later in 20 age-matched controls. Data were expressed as z scores (SD, mean +/- sem) derived from 405 postmenopausal women. In patients with hypoparathyroidism, bone mass z score of the third lumbar vertebra (vertebral body plus posterior processes) was higher than zero by PA scanning (1.26 +/- 0.58 SD, P < 0.05) and lateral scanning (1.04 +/- 0.60 SD, P = 0.1), and higher at the trabecular-rich vertebral body (1.02 +/- 0.47 SD, P = 0.07) and predominantly cortical posterior processes (0.98 +/- 0.66 SD, P = 0.1) determined by lateral scanning. The BMD z scores were higher than zero at the femoral neck (0.89 +/- 0.48 SD, P = 0.09), but not at the femoral midshaft (0.45 +/- 0.60, NS) and distal radius (0.04 +/- 0.51, NS). During follow-up, femoral neck BMD decreased in controls but not in patients with hypoparathyroidism (slope, -0.00818 +/- 0.00496 g/cm2/year vs. 0.00907 +/- 0.00583 g/cm2/year, respectively, P = 0.06). There was no change in lumbar spine BMD in either group. In 25 women with primary hyperparathyroidism, there were no deficits in BMD at the third lumbar vertebra (vertebral body plus posterior processes) by PA or lateral scanning. By lateral scanning, BMC was increased at the vertebral body (0.64 +/- 0.31 SD, P < 0.01) and reduced at the posterior processes (-0.65 +/- 0.26 SD, P < 0.05). BMD was lower at the midshaft of the femur (-0.82 +/- 0.37 SD, P < 0.05) and at the distal radius (-0.68 +/- 0.20 SD, P < 0.01), but not at the femoral neck (-0.08 +/- 0.20 SD, NS). Longitudinal data were unavailable in hyperparathyroid patients. In summary, trabecular bone is increased by both PTH deficiency and excess. Cortical bone loss is slowed by PTH deficiency and accelerated by PTH excess so that suppression of PTH may reduce age-related bone loss and the risk of fracture. Assessment of BMD in PTH deficiency and excess requires the separate study of cortical and trabecular bone.

Background There are few dual X-ray absorptiometry (DXA) studies on periacetabular bone density changes after cup implantation. This study was designed to analyze the load-transfer mechanism and stress pattern of periacetabular cortical and cancellous bone after implantation of a ihemispherical titanium alloy press-fit cup with alumina-alumina pairing in vivo. We introduced a novel method of computed tomography (CT)-assisted osteodensitometry.Method We investigated 26 hips (26 patients) with osteoarthritis using conventional sequential CT examinations performed within the first 10 days after implantation, and after a mean period of 1.1 years postoperatively. Bone density of full, cancellous and cortical bone (mgCaHA/mL) was measured.Results At the time of follow-up, the mean bone density values of the cortical bone cranial to the cup increased by 3.6% (p = 0.03) while the cancellous bone density decreased by 18%. Cancellous bone loss was greater in the region ventral to the cup (–35%) than in the dorsal region (–30%). Cortical bone density decreased ventral to the cup (–6.4%). All these changes were statistically significant. The bone density changes in the dorsal cortical region were not significant.Interpretation The method presented is an excellent tool for detailed measurement of bone density changes around the cup after total hip arthroplasty, and allows a thorough assessment of stress shielding phenomena in vivo. The hemispherical titanium alloy press-fit cup is a rigid implant which stress shields cancellous bone and enhances load transfer to the cranial cortical bone. Further investigations will demonstrate the impact these factors have on the long-term results of the implant, and may allow a type-related predictable prognosis of the longevity of the prosthesis.

Inhibition of cortical and cancellous bone formation in glucocorticoid-treated OVX sheep

Biomechanical effectiveness of cortical bone thickness on orthodontic microimplant stability: An evaluation based on the load share between cortical and cancellous bone

We measured indices of bone volume (cancellous and cortical) and bone surface (cancellous, endocortical, and intracortical) in intact, full-thickness transiliac bone biopsies obtained from 47 healthy white women (23 premenopausal and 24 postmenopausal) and 82 patients with postmenopausal osteoporosis. In the normal subjects there was the expected loss of cancellous bone with age, best shown by a reduction in bone surface/tissue volume, but no fall in cortical thickness with age despite a significant reduction in forearm bone density measured by single-photon absorptiometry. Bone surface/bone volume was about four times higher in cancellous than in cortical bone, and cancellous bone contributed about one-third of the total bone volume and about two-thirds of the bone surface when related to the core volume referent. In the osteoporotic patients, core width, an index of iliac bone thickness at the biopsy site, was reduced by 10%, but we could not determine whether this was the result of compaction of the core or of bone slenderness. All indices of bone volume, cortical as well as cancellous, were significantly smaller, as were the values for forearm bone densitometry; the relative deficits at different sites depended on whether they were expressed as percentages or as zeta scores. Bone surface/bone volume was increased in both cancellous and cortical bone, but bone surface/tissue volume was reduced in cancellous bone and increased in cortical bone. The proportions of total bone volume and surface contributed by cancellous and cortical bone were almost the same as in normal postmenopausal women.(ABSTRACT TRUNCATED AT 250 WORDS)

The aims of this study performed in ewes were: (1) to confirm in this animal model the effects on bone of ovariectomy (OVX) alone or associated with Lentaron (L), a potent peripheral aromatase inhibitor, used to amplify the effects of OVX and (2) to evaluate the effects of a new selective estrogen receptor modulator (SERM; MDL 103,323) on bone remodeling. Thirty-nine old ewes were divided into five groups: sham (n = 7); OVX (n = 8); OVX + L (n = 8); OVX + L + MDL; 0.1 mg/kg per day (n = 8); and OVX + L + MDL 1 mg/kg per day (n = 8). The animals were treated for 6 months. Biochemical markers of bone turnover (urinary excretion of type 1 collagen C-telopeptide [CTX], serum osteocalcin [OC], and bone alkaline phosphatase [BAP]) were measured each month. Bone biopsy specimens were taken at the beginning and after death at the end of the experiment. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA) on the lumbar spine and femur. OVX induced a significant increase in biochemical markers. This effect was the highest after 3 months for CTX (+156% vs. sham) and after 4 months for OC and BAP (+74% and +53% vs. sham, respectively). L tended to amplify the effect of OVX on OC and BAP. OVX induced significant increases in the porosity, eroded, and osteoid surfaces in cortical bone but no effect was observed in cancellous bone. MDL treatment reduced the bone turnover as assessed by bone markers, which returned to sham levels as well as histomorphometry both in cortical and in cancellous bone. Cancellous osteoid thickness decreased by 27% (p < 0.05), mineralizing perimeter by 81% (p < 0.05), and activation frequency by 84% (p < 0.02) versus OVX + L. Femoral and spinal BMD were increased by MDL and tended to return to the sham values. The effects of OVX on bone turnover were different on cortical and cancellous bone. These effects on cortical bone were reflected by changes in biochemical markers. MDL markedly reduces bone turnover and increases BMD suggesting that this new agent may prevent postmenopausal bone loss.

SummaryThirteen pairs of tibiae were excised from adult mongrel dogs following a mean recovery period of 24.2 weeks after unilateral total hip arthroplasty (THA). Prior to euthanasia, peak vertical dynamic load, as a percent of body weight, was determined for each limb at a walking pace. Four contiguous proximal sections and one transverse cortical midshaft section, 5mm thick, were harvested from each tibia. Contact Faxitron radiographs of the sections were quantified, using video digitizing software, to compare mean apparent density measures between the treated (THA) and intact limbs. There was a significant difference in mean apparent density of cancellous bone with the treated limb having a lower apparent density than the intact limb. The mean cortical area at the midshaft was significantly lower and the medullary area significantly higher among tibiae from the treated side, as compared to the contra-lateral tibiae. Resistance to bending and tension at the midshaft of each bone were determined using the second moment of area about cranio-caudal (Ix) and mediolateral (Iy) axes. The mean Iy values for the treated limbs were significantly lower than for the intact limbs. Therefore, measurable adaptive bone remodeling appears to be present in both cancellous and cortical bone in the tibia due to decreased mechanical loading.

The goal of this study was to evaluate the effects of chronically-elevated male levels of the potent androgen testosterone on the quality and quantity of both cancellous and cortical bone in a young (mean age 8.0 years), nonhuman female primate model (M. fascicularis). Thirteen intact female monkeys received continuous testosterone supplementation via subcutaneous implants over a 24-month period. A group of 16 untreated, intact, age-matched female monkeys served as controls. At sacrifice, the lumbar vertebrae and femora were recovered in order to analyze the bone mineral quality and quantity of cancellous and cortical bone, respectively, and compared to the control group. Mineralization profiles of the vertebrae and femora were obtained using the density fractionation technique. Chemical analysis of the three largest fractions retrieved by density fractionation was performed to evaluate differences in %Ca, %P, Ca/P ratio, and mineral content (%Ca + %PO4) between the control and experimental groups. In addition, unfractionated bone powder was examined by X-ray diffraction to identify any changes in crystal size. Coronal sections of vertebrae were analyzed for structural parameters using histomorphometry and image analysis. Cross sections taken at the midshaft diaphyseal femora were analyzed for structural macroscopic and intracortical parameters. A nonsignificant shift in the mineralization profile of the vertebrae was observed whereas there was a significant shift in the mineralization profile towards more dense bone in the treated femora as compared with controls (P < 0.05). There was no difference in terms of size/strain of the cortical or cancellous bone crystal as detected by X-ray diffraction. There was a trend towards an increase in cancellous bone area (B.Ar.) in the testosterone-treated vertebrae (P = 0.08) as compared with controls. The architecture of the cancellous bone remained nonsignificantly different between the treatment and control groups as evaluated by image analysis. There was a decrease in osteoid perimeter (P = 0.05) in the experimental group as compared with controls. There was a significant decrease in eroded perimeter measurements in the experimental group as compared with controls (P < 0.03). Although there was a trend towards an increase in cancellous bone area, mineralization was not significantly different in the vertebrae of testosterone-treated female monkeys, indicating that the newly-formed bone tissue became relatively normally mineralized over the two-year period. An increase in bone area, with indices of an overall decreased remodelling pattern as compared with controls, suggests that cancellous bone in the young, nonhuman female primate had been receptive to supraphysiologic levels of testosterone supplementation over the two-year period. There was a trend for an increase in cortical bone area and width with an increased periosteal perimeter in the testosterone-treated group as compare with controls. There was an increase in intracortical remodelling activity with a significant increase in percent porosity (P < 0.05), osteonal bone (P < 0.05), and mean wall width (P < 0.05) in the testosterone-treated group. In conclusion, the cancellous bone from female monkeys appeared to respond to the antiresorptive stimulus of male levels of testosterone with significantly diminished turnover parameters in this compartment. In contrast, the cortical bone compartment responded by displaying significant intracortical remodelling over a two-year period.

Single-dose pharmacokinetics of vancomycin in porcine cancellous and cortical bone determined by microdialysis

ObjectiveThe aim of this retrospective study was to evaluate the pre- and postsurgical bone densities at alveolar and extra-alveolar sites following two-jaw orthognathic surgery.MethodsThe sample consisted of 10 patients (mean age, 23.2 years; range, 18.0–27.8 years; 8 males, 2 females) who underwent two-jaw orthognathic surgery. A three-dimensional imaging program (Invivo 5) was used with multidetector computed tomography images taken pre- and postoperatively (obtained 32.3 ± 6.0 days before surgery and 5.8 ± 2.6 days after surgery, respectively) for the measurement of bone densities at the following sites: (1) alveolar bone in the maxilla and mandible, (2) extra-alveolar sites, such as the top of the head, menton (Me), condyle, and the fourth cervical vertebrae (C4).ResultsWhen pre- and postsurgical bone densities were compared, an overall tendency of decrease in bone density was noted. Statistically significant reductions were observed in the densities of cancellous bone at several areas of the maxillary alveolar bone; cortical and cancellous bone in most areas of the mandibular alveolar bone; cortical bone in Me; and cancellous bone in C4. There was no statistically significant difference in bone density in relation to the depth of the alveolar bone. In a comparison of the bone densities between groups with and without genioplasty, there was almost no statistically significant difference.ConclusionsAccelerated tooth movement following orthognathic surgery may be confirmed with reduced bone density. In addition, this study could offer insights into bone metabolism changes following orthognathic surgery, providing direction for further investigations in this field.

The comparative holding strength of cannulated screws (CS) versus solid core screws (SCS) has not been reported, although differences exist in the respective diameters of their outer thread and pilot drill holes. Our objectives were to characterize these differences and determine the holding power of CS compared with SCS in cortical and cancellous bone. The dimensions of the Synthes (Paoli, PA) 3.5-mm SCS, 3.5-mm CS, 6.5-mm SCS, and 7.0-mm CS were measured, and the cross-sectional area for thread purchase was calculated. Using adult canine femurs, small-fragment 3.5-mm SCS were inserted in cortical (midshaft) and cancellous (condyle) bone of one limb, and CS were placed in similar locations in the contralateral limb. The same technique was used for large-fragment CS and SCS. Pull-out testing was performed using an MTS machine (MTS Systems, Minneapolis, MN) with axial loads applied at 5 mm/s, and data were analyzed to determine the effects of screw type, location, and size. Differences in CS versus SCS design result in higher cross-sectional areas available for SCS thread purchase. Yet no significant differences exists between screw types (SCS vs. CS) in either cortical or cancellous bone. In cancellous bone, large-fragment screws required more force to pull out than did small screws (p = 0.000). The mean force required to pull out small-fragment screws was higher in cortical bone than in cancellous bone (p = 0.000). These data suggest that the clinical decision to use CS versus SCS should not be based on pull-out strength.

Hypoxemia has been recognized as a risk factor for bone loss. The aim of the present study is to investigate the relationship of bone mass and density measures with anemia and hemoglobin levels in a large sample of older community-dwelling persons. The study is based on data from 950 participants enrolled in the "Invecchiare in Chianti" (Aging in the Chianti area, InCHIANTI) study. All the analyses were performed considering continuous hemoglobin levels as well as the dichotomous anemia variable (defined according to WHO criteria as hemoglobin < 12 g/dl in women and < 13 g/dl in men). A peripheral quantitative computerized tomography (pQCT) scan of the right calf was performed in all participants to evaluate total bone density, trabecular bone density, cortical bone density, and the ratio between cortical and total bone area. Linear regression analyses were used to assess the multivariate relationship of pQCT bone measures with anemia and hemoglobin levels after adjustment for demographics, chronic conditions, muscle strength and biological variables. Participants were 75.0 (SD 6.9) years old. In our sample, 101 participants (10.6%) were anemic. In women, coefficients from adjusted linear regression analyses evaluating the association between pQCT bone measures (per SD increase) and hemoglobin levels/anemia showed significant associations of anemia with total bone density (beta = -0.335, SE = 0.163; P = 0.04) and cortical bone density (beta = -0.428, SE = 0.160; P = 0.008). Relationships with borderline significance were found for the associations of anemia with trabecular bone density and the ratio between cortical and total bone area. Significant associations were found between hemoglobin levels and trabecular bone density (beta = 0.112, SE = 0.049; P = 0.02), total bone density (beta = 0.101, SE = 0.046; P = 0.03), cortical bone density (beta = 0.100, SE = 0.046; P = 0.03) and the ratio between cortical bone and total area (beta = 0.092, SE = 0.045; P = 0.04). In men, significant associations were found for hemoglobin levels with total bone density (beta = 0.076, SE = 0.036; P = 0.03) and cortical bone density (beta = 0.095, SE = 0.41; P = 0.02). A borderline significance was reported for the association between anemia and cortical bone density. We concluded that anemia and low hemoglobin levels are negatively and independently associated with bone mass and density. The bone loss associated with hemoglobin levels mainly occurs in the cortical bone. Women with lower hemoglobin levels demonstrate a higher bone loss than male counterparts.

In order to identify pertinent models of cortical and cancellous bone regeneration, we compared the kinetics and patterns of bone healing in mouse femur using two defect protocols. The first protocol consisted of a 0.9-mm-diameter through-and-through cortical hole drilled in the mid-diaphysis. The second protocol was a 0.9-mm-diameter, 1-mm-deep perforation in the distal epimetaphyseal region, which destroyed part of the growth plate and cancellous bone. Bone healing was analyzed by ex vivo micro-computerized X-ray tomography and histology. In the diaphysis, the cortical gap was bridged with woven bone within 2 weeks. This newly formed bone was rapidly remodeled into compact cortical bone, which showed characteristic parameters of intact cortex 4 weeks after surgery. In the epimetaphysis, bone formation was initiated at the deepest region of the defect and spread slowly toward the cortical gap. In this position, newly formed bone quickly adopted the characteristics of trabecular bone, whereas a thin compact wall was formed at its external border, which reached the density of intact cortical bone but failed to bridge the cortical gap even 13 weeks after surgery. This comparative study indicates that the diaphyseal defect is a model of cortical bone healing and that the epimetaphyseal defect is a model of cancellous bone repair. These models enable experimental genetics studies to investigate the cellular and molecular mechanisms of spontaneous cortical and cancellous bone repair and may be useful for pharmacological studies.

The aim of this study was to evaluate the normal distribution of sodium fluoride-18 (NaF-18) and to clarify the differences in uptake according to location and the type of the bone using positron emission tomography (PET) / computed tomography (CT). We retrospectively reviewed NaF-18 PET/CT images from 30 patients with hip joint disorders. PET/CT scans were performed 40 min after injection of approximately 185 MBq of NaF-18. To evaluate the relationship between the distribution of NaF-18 uptake and bone density, we compared the maximum standardised uptake values (SUVmax) on PET and the Hounsfield Units (HUs) on CT of the lumbar vertebra, ilium, and proximal and distal femurs. Regions of interests were defined both outside and inside the cortical bone to measure whole bone and cancellous bone only, respectively. The distribution of NaF-18 differed according to the skeletal site. The lumbar vertebra showed the highest SUVmax for both whole bone and cancellous bone, followed by the ilium, proximal femur, and distal femur. The bones differed significantly in SUVmax. The distal femur showed the highest HU, followed by the proximal femur, ilium, and vertebra. Profile curve analyses demonstrated that the cancellous bones showed higher SUVmax and lower HU than the cortical bones. Our results demonstrate the difference in NaF-18 uptake between cancellous and cortical bones, which may explain differences in uptake by location. NaF-18 uptake does not appear to be strongly correlated with bone density, but rather with bone turnover and blood flow.