Low level irradiation in mice can lead to enhanced trabecular bone morphology

Charged particle radiation such as iron ions and their secondary fragmentation products are of particular concern to the skeleton due to their high charge and energy deposition. However, little is known about the long-term effects of these particles on trabecular and cortical bone morphology when applied at relatively low levels. We hypothesized that even a 4.4 cGy dose of a complex secondary iron ion radiation field will compromise skeletal quantity and architecture in adult mice. One year after radiation exposure and compared to age-matched controls, 4.4 cGy irradiated mice had 51 % more trabecular bone, 56 % greater trabecular bone volume fraction, 16 % greater trabecular number, and 17 % less trabecular separation in the distal metaphysis of the femur. Similar to the metaphysis, trabecular bone of the distal femoral epiphysis in 4.4 cGy mice had 33 % more trabecular bone, 31 % greater trabecular bone volume fraction, and a 33 % smaller structural model index. Cortical bone morphology, whole bone mechanical properties, and lower leg muscle mass were unaffected. When compared to two additional groups, irradiated at either 8.9 or 17.8 cGy, a (negative) dose response relationship was observed for trabecular bone in the metaphysis but not in the epiphysis. In contrast to our original hypothesis, these data indicated that a secondary field of low-level, high-linear energy transfer iron radiation may cause long-term augmentation, rather than deterioration, of trabecular bone in the femoral metaphysis and epiphysis of mice.     

Thyroparathyroidectomy modifies the skeletal response to aluminum loading in the rat

Diminished parathyroid hormone (PTH) secretion may contribute to the accumulation of aluminum (Al) in bone and to impaired bone formation in Al-related bone disease. Therefore, intact (AL, N = 9) and thyroparathyroidectomized (TPTX-AL, N = 9) rats were given intraperitoneal injections of Al, 2 mg/day, for 42 days; intact control (C, N = 11) and TPTX control (TPTX-C, N = 9) animals received i.p. injections of vehicle only. Quantitative bone histology and measurements of mineralized bone formation (Rbf) using double tetracycline labeling were done for cortical and for trabecular bone; trabecular bone aluminum content (BA) was determined by histochemical methods. BA did not differ between AL and TPTX-AL, 33 +/- 13% versus 39 +/- 14%, and Rbf decreased similarly from control values in both Al-treated groups. In contrast, osteoid production was impaired to a greater extent in TPTX-AL than in AL. Thus, osteoid area and osteoid seam width were each lower in TPTX-AL than in TPTX-C; these values did not differ between AL and C. TPTX can aggravate Al induced reductions in osteoid synthesis, and low serum PTH levels may contribute to the pathogenesis of aplastic bone. However, reductions in Rbf during Al loading are not mediated by PTH.     

Clinical and histologic features of iron-related bone disease in dialysis patients

Forty-eight dialysis patients undergoing bone biopsy were analyzed for clinical history, blood biochemical values, bone histologic findings, bone aluminum content (BAC), bone iron content (BIC), bone iron stores, and histochemical staining of bone aluminum and bone iron. Four patients had significant trabecular bone iron staining alone; eight patients had significant bone iron and bone aluminum staining; 13 patients had significant bone aluminum staining alone; and 23 patients showed no significant bone aluminum or iron staining. Patients with significant bone iron staining were younger (37.4 +/- 5.3 years v 53.2 +/- 2.3 years, P less than 0.01, mean +/- SEM) and were more likely to be anephric (P less than 0.001) and to have a history of prior renal transplantation (P less than 0.10). The 12 patients with significant bone iron staining had received more blood transfusions than those without bone iron staining (96 +/- 22.8 U v 22 +/- 5.8 U, P less than 0.005). Patients with bone iron accumulation had higher levels of serum ferritin (3,594 +/- 1,138.4 micrograms/L [ng/mL] v 265 +/- 60.1 micrograms/L, P less than 0.01) and lower levels of immunoreactive parathyroid hormone (iPTH) (349 +/- 150 microLEq/mL v 1,801 +/- 397 microLEq/mL [386 +/- 166 pmol/L v 1,990 +/- 439 pmol/L], P less than 0.005). BIC was also higher in these patients (1,008 +/- 149 micrograms iron/g bone v 300 +/- 46.5 micrograms iron/g bone, P less than 0.001) and higher than normal BIC (256 +/- 44.2 micrograms iron/g bone, eight normals). Bone marrow iron stores were positively related to serum ferritin levels (P less than 0.01) and trabecular bone iron staining (P less than 0.10). All 13 patients with osteomalacia demonstrated significant bone aluminum staining; seven of these patients demonstrated concomitant significant iron staining. Fourteen of 15 patients with severe hyperparathyroidism showed no significant iron or aluminum staining. Our data indicate that iron will probably not accumulate within bone until all other storage sites (eg, bone marrow) are fully saturated. The presence of lower levels of iPTH in iron-overloaded patients raises the possibility that iron overload may induce a state of relative hypoparathyroidism. The most important determinant for the presence of osteomalacia seems to be the presence of significant aluminum staining. No specific bone histologic finding was related to the presence of bone iron staining, but the rarity of isolated significant bone iron staining makes it difficult to evaluate bone histologic diagnoses that might be solely attributable to iron.     

Metabolic bone disease with and without osteomalacia after intestinal bypass surgery: a bone histomorphometric study

We performed iliac bone histomorphometry after in vivo double tetracycline labeling 3-14 years after intestinal bypass surgery for obesity in 21 patients, selected because of clinical suspicion of metabolic bone disease, and compared the results with those of 40 age-matched normal control subjects. Osteomalacia defined by rigorous kinetic criteria was found in six cases, histologic features of secondary hyperparathyroidism without significantly impaired mineralization in one case, and possible osteomalacia masked by impaired matrix synthesis in one case. In the patients with definite osteomalacia, nonfracture bone pain was more frequent, corrected plasma calcium lower, plasma alkaline phosphatase and magnesium higher, and secondary hyperparathyroidism more severe than in the other patients. In the patients without osteomalacia there was a 24.5% reduction in trabecular bone volume compared to the controls; in contrast to age-related bone loss and post-menopausal osteoporosis, this was due mainly to reduction in the thickness rather than the density of trabecular plates. About two-thirds of the reduction in trabecular thickness was due to reduction in interstitial bone thickness, representing the cumulative effect of increased depth of osteoclastic resorption cavities, probably due in part to secondary hyperparathyroidism. About one-third of the reduction in trabecular thickness was the result of reduced mean wall thickness, representing insufficient osteoblastic matrix synthesis, probably due in part to malabsorption of an unidentified nutrient necessary for normal bone health. Resorption indices were not increased at the time of the biopsy, but there were persistent defects in the recruitment and activity of osteoblasts. Clinically significant bone loss after intestinal shunt surgery, as in several other clinical situations, results from the combined effects of an unsustained increase in bone resorption and a sustained decrease in bone formation.     

Low-level mechanical vibrations can influence bone resorption and bone formation in the growing skeleton

Short durations of extremely small magnitude, high-frequency, mechanical stimuli can promote anabolic activity in the adult skeleton. Here, it is determined if such signals can influence trabecular and cortical formative and resorptive activity in the growing skeleton, if the newly formed bone is of high quality, and if the insertion of rest periods during the loading phase would enhance the efficacy of the mechanical regimen. Eight-week-old female BALB/cByJ mice were divided into four groups, baseline control (n = 8), age-matched control (n = 10), whole-body vibration (WBV) at 45 Hz (0.3 g) for 15 min day(-1) (n = 10), and WBV that were interrupted every second by 10 of rest (WBV-R, n = 10). In vivo strain gaging of two additional mice indicated that the mechanical signal induced strain oscillations of approximately 10 microstrain on the periosteal surface of the proximal tibia. After 3 weeks of WBV, applied for 15 min each day, osteoclastic activity in the trabecular metaphysis and epiphysis of the tibia was 33% and 31% lower (P <0.05) than in age-matched controls. Bone formation rates (BFR.BS(-1)) on the endocortical surface of the metaphysis were 30% greater (P <0.05) in WBV than in age-matched control mice but trabecular and middiaphyseal BFR were not significantly altered. The insertion of rest periods (WBV-R) failed to potentiate the cellular effects. Three weeks of either WBV or WBV-R did not negatively influence body mass, bone length, or chemical bone matrix properties of the tibia. These data indicate that in the growing skeleton, short daily periods of extremely small, high-frequency mechanical signals can inhibit trabecular bone resorption, site specifically attenuate the declining levels of bone formation, and maintain a high level of matrix quality. If WBV prove to be efficacious in the growing human skeleton, they may be able to provide the basis for a non-pharmacological and safe means to increase peak bone mass and, ultimately, reduce the incidence of osteoporosis or stress fractures later in life.     

Alteration of femoral bone morphology and density in COX-2-/- mice

A role of COX-2 in pathological bone destruction and fracture repair has been established; however, few studies have been conducted to examine the involvement of COX-2 in maintaining bone mineral density and bone micro-architecture. In this study, we examined bone morphology in multiple trabecular and cortical regions within the distal and diaphyseal femur of 4-month-old wild-type and COX-2-/- mice using micro-computed tomography. Our results demonstrated that while COX-2-/- female mice had normal bone geometry and trabecular microarchitecture at 4 months of age, the male knockout mice displayed reduced bone volume fraction within the distal femoral metaphysis. Furthermore, male COX-2-/- mice had a significant reduction in cortical bone mineral density within the central cortical diaphysis and distal epiphysis and metaphysis. Consistent with the observed reduction in cortical mineral density, biomechanical testing via 4-point-bending showed that male COX-2-/- mice had a significant increase in postyield deformation, indicating a ductile bone phenotype in male COX-2-/- mice. In conclusion, our study suggests that genetic ablation of COX-2 may have a sex-related effect on cortical bone homeostasis and COX-2 plays a role in maintaining normal bone micro-architecture and density in mice.     

Parathyroid hormone response to hypocalcemia in hemodialysis patients with osteomalacia

The parathyroid hormone response to hypocalcemia was investigated in hemodialysis patients with osteomalacia and compared to those with osteitis fibrosa. Hypocalcemia was induced during hemodialysis by employing a dialysate devoid of calcium. Patients with osteomalacia had a blunted maximum amino terminal parathyroid hormone response (+/- SD) (0.39 +/- 0.33 vs. 0.87 +/- 0.53 ng/ml, P less than 0.05) and maximum carboxy terminal parathyroid hormone response (+/- SD) (0.36 +/- 0.20 vs. 0.84 +/- 0.47, P less than 0.02) to hypocalcemia. The decline in plasma calcium was greater in patients with osteomalacia at 90 (P less than 0.05), 120 (P less than 0.01), and 150 min (P less than 0.01). In osteomalacia patients the surface density of histologically detectable trabecular bone aluminum correlated directly with the percent relative osteoid volume (P less than 0.005) and inversely with the maximum amino terminal parathyroid hormone response to hypocalcemia (P less than 0.025). These results suggest that hemodialysis patients with osteomalacia have diminished secretion of parathyroid hormone and a decreased ability to restore plasma calcium homeostasis during hypocalcemia.     

The microscopic morphology of fluoride-induced bone

To characterize further the bone changes in osteoporotic patients treated by a combined calcium, vitamin D, and sodium fluoride therapy regimen, full-thickness transilial undecalcified bone biopsy specimens from ten postmenopausal white women treated for idiopathic osteoporosis for 18-24 months were compared with those from ten age-, sex-, and race-matched untreated control subjects using standard light microscopy and histomorphometry. Statistically significant bone changes in the treated group consisted of cortical and trabecular new bone formation juxtaposed on underlying normal lamellar bone (p less than 0.001). The new bone showed increased osteocytic cellularity (p less than 0.001), irregular arrangement of osteocytes (p less than 0.001), enlarged osteocyte lacunae (p less than 0.001), and periosteocytic hematoxylinophilic staining intensity (p less than 0.001). Increases were also noted in trabecular bone volume (p less than .025), trabecular osteoid surface (p less than 0.001), and trabecular osteoid volume (p less than 0.001). Osteoid calculations were significantly less than those in the clinical and chemical osteomalacia observed in the authors' laboratory (p less than 0.01). Osteoclastic resorptive activity was increased (p less than .001), but no evidence of hyperparathyroidism was noted. These histologic and histomorphometric changes indicate accretion of new bone but with distinctly abnormal matrix characteristics. These are changes considered characteristic of the treatment and are pathologic markers of fluoride-induced abnormal bone formation.     

Relationships between marrow fat and bone turnover in ovariectomized and intact rats

It is known that marrow fat content increases in a variety of osteoporoses. This study sought to clarify this phenomenon by combining bone and marrow histomorphometry, and to determine (1) whether the marrow fat increase follows or precedes diminishment of bone volume, and (2) whether the increase in fat volume is due to adipocyte growth or proliferation. The relationship between marrow fat content and bone turnover was studied in the metaphysis and epiphysis of the proximal tibia in 20 ovariectomized and 20 intact 200 gm Sprague-Dawley rats. The results were examined after one and three months. The epiphysis had greater trabecular bone volume than the metaphysis. The metaphysis exhibited a decrease in bone volume with time; the epiphysis did not. Following ovariectomy, the bone volume diminished twice as much in the metaphysis as in the epiphysis. In the epiphysis, as bone volume fraction fell following ovariectomy, the vacated space was filled by both hemopoietic and adipose tissue. In the metaphysis, space-filling was time-dependent: hemopoietic tissue at one month and adipose tissue at three months. Marrow fat content increased with both time and ovariectomy in the metaphysis, but only with time in the epiphysis. Thus, marrow fat increased after bone volume began to decline in the metaphysis, and not at all in the epiphysis. Ovariectomy increased erosion surface in both the epiphysis and the metaphysis, but bone formation rate was increased only in the epiphysis. There was a reciprocal relationship between marrow fat content and bone formation rate.     

Heterogeneity of human bone

Matched samples of bone from the lumbar spine and tibia were obtained at autopsy from three adult males who had no known evidence of metabolic bone disease at the time of their demise. The soluble noncollagenous bone proteins were quantitatively extracted from these samples and assayed for the relative content of two bone-associated proteins, osteocalcin and osteonectin. When compared to trabecular bone, cortical bone had higher levels of osteocalcin and much lower levels of osteonectin. When concentration is expressed per gram of dried bone, the osteocalcin excess in cortical bone ranged from 30- to 32-fold, and the osteonectin excess in trabecular bone ranged from 21- to 47-fold. These differences were significant (P less than 0.01) using analysis of variance. We conclude that the human skeleton is not homogeneous with regard to these biochemical markers and that cortical and trabecular bone are biochemically quite distinct. This implies that these two types of bone may be subject to distinct regulatory mechanisms and that global assessments of skeletal function and bone quality based upon soluble markers should be applied with caution. The data also imply that a differential assessment of skeletal performance may be possible using biochemical serum markers.     

Discordance between bone turnover and bone loss: effects of aging and ovariectomy in the rat.

Mechanical strain maintains bone architecture even under conditions of increased bone turnover such as occurs with ovarian hormone deficiency. The rat distal femur contains two sites that apparently experience different levels of mechanical strain and therefore the rat is a suitable model for investigating such effects. The femoral epiphysis experiences higher strain energy compared with the metaphysis and we report the effects of aging between 7 and 12 months and the postovariectomy effects over the same time period on cancellous bone variables measured at these two sites. Age-related bone loss in sham-operated (Sham) animals occurred in both regions, with a greater fall in the metaphysis than in the epiphysis (trabecular bone volume [BV/TV, %] Mean [SEM] Metaphysis: day 0, 25. 9 [2.4]; day 150, 8.8 [1.3]: Epiphysis: day 0, 44.8 [1.7]; day 150, 36.7 [1.4] [p < 0.0001]). With ovariectomy (OVX) there was a 73% reduction in cancellous bone at the metaphysis compared with no specific loss at the epiphysis (BV/TV [%] OVX: Metaphysis: day 150, 2.4 [0.4] [p < 0.01 compared with Sham]: Epiphysis: day 150 29.3 [2. 7] [NS]). Osteoblast cell activity and osteoclast surface were increased after ovariectomy in both regions. The mineral apposition rate decreased at 9.5 months of age in both regions (p < 0.0001), independent of ovariectomy, and was coincident with a reduction in trabecular number in the epiphyses of both operative groups and in the metaphysis of the ovary-intact group. These data suggest that local mechanical strain governs bone balance with aging and that architectural changes resulting from age-related bone loss may mirror those following estrogen deficiency but occur via a different cellular mechanism.     

The proportion of trabecular bone in human vertebrae

The proportion of trabecular bone in human cadaver vertebrae was assessed by anatomic dissection. Thirty-two whole thoracic and lumbar vertebrae were obtained from 10 normal human postmenopausal female cadavers, 14 from 4 normal adult human male cadavers of similar age, and 8 from one female osteoporotic cadaver. Each vertebra was opened by saw cuts and separated into four tissue types: (1) body trabecular bone and marrow; (2) body cortical bone; (3) vertebral arch trabecular bone and marrow; and (4) vertebral arch cortical bone. Calcium was determined in each tissue type for each vertebra by ashing and atomic absorption spectrophotometry. Trabeculae accounted for 24.4 +/- 4.5% of the total calcium in whole female vertebrae, and 18.8 +/- 4.4% in whole male vertebrae (p less than 0.001). The body averaged 41.8% trabecular bone in females and 33.5% in males. The arch averaged 9.7% trabecular bone in females and 4.9% in males. The proportion of trabecular bone in the whole vertebrae in the single osteoporotic spine was 28.5 +/- 3.2%, a value not significantly different from the trabecular fraction in normal females. These data indicate that whole human thoraco-lumbar vertebrae are composed of a substantially lower proportion of trabecular bone than is usually assumed, and they suggest that cortical and trabecular bone are eventually lost in equal proportion from the vertebrae during the development of spinal osteoporosis. These results are important for the interpretation of data from noninvasive bone measurement techniques that evaluate the spine, and they suggest that studies of this type are important for any site where noninvasive bone mass measurement is done.     

Antero-postero differences in cortical thickness and cortical porosity of T12 to L5 vertebral bodies

OBJECTIVE: This study will investigate interrelationships between the cortical shell and cancellous bone trabecular thickness, in vertebral bodies. METHODS: One hundred and sixty vertebral bodies from T12 to L5 were obtained at autopsy. The average age of the cohort was 59.3+/-22.1 years (range = 20-94 years). Cortical thickness, cortical porosity and trabecular thickness from the adjacent cancellous bone were measured. RESULTS: At the mid-vertebral body anterior cortical thickness was significantly greater than posterior cortical thickness (524 +/- 352 vs. 370 +/- 283 microm, respectively, P < 0.0001) and mid-anterior cortical porosity was significantly less than mid-posterior cortical porosity (24 +/- 14% vs. 32 +/- 16%, respectively, P < 0.0001). There were no anterior/posterior differences in trabecular thickness of the cancellous bone adjacent to the cortical walls. CONCLUSION: This study provides a novel perspective of T12 to L5 vertebral body bone, where measurement of cortical thickness and cortical porosity in a cohort of skeletally normal individuals revealed structural differences between load bearing anterior and posterior cortical walls. The data suggest that modulators of change to vertebral body bone may affect the cortical and trabecular bone differently. The relationships between cortical and cancellous bone suggest that the middle sectors of the vertebral body play a critical role in load bearing.     

Effect of aluminum and parathyroid hormone on osteoblasts and bone mineralization in chronic renal failure

Bone aluminum, quantitative bone histology, and plasma parathyroid hormone (PTH) were compared in 29 patients undergoing chronic hemodialysis. Histologic techniques included double tetracycline labeling and histochemical identification of osteoclasts and osteoblasts. Bone aluminum was measured chemically by flameless atomic absorption spectrophotometry, and histochemically. When measured chemically, the bone aluminum was 67 +/- 46 (SD) mg/kg dry weight (normal 2.4 +/- 1.2 mg/kg); histochemically, aluminum was present at 2.9 +/- 4.4% of trabecular surface. The biochemical and histochemical results agreed well (r = 0.80, P less than 0.001). No double tetracycline labels were seen at the mineralization front where aluminum was deposited, indicating cessation of mineralization at these sites. The osteoblast surface correlated positively with plasma PTH (r = 0.67, P less than 0.001) and negatively with bone aluminum level (r = -0.42, P less than 0.05). Multiple linear regression showed a correlation of aluminum with osteoblasts additional to that of PTH, consistent with a direct effect of aluminum in depressing osteoblast numbers. Though a relationship between PTH and chemically determined bone aluminum level could not be demonstrated, there was a negative correlation between osteoclast count and aluminum, and the nine patients with severe hyperparathyroid bone disease had lower chemically determined aluminum levels than the other patients. These results suggest that aluminum (a) directly inhibits mineralization, (b) is associated with decreased PTH activity and hence osteoblast numbers, and (c) directly reduces osteoblast numbers. In addition to inducing severe, resistant osteomalacia, aluminum appears to contribute to the mild osteomalacia commonly seen in renal failure, characterized by extensive thin osteoid and low tetracycline and osteoblast surfaces.     

Decreased bone remodeling and porosity are associated with improved bone strength in ovariectomized cynomolgus monkeys treated with denosumab, a fully human RANKL antibody

This study examined the effects of denosumab, an anti-RANKL antibody that inhibits bone resorption, on bone histomorphometry in adult ovariectomized cynomolgus monkeys (OVX cynos). A month after surgery, OVX cynos were treated with subcutaneous vehicle (OVX-Veh) or denosumab (25 or 50mg/kg/month) for 16months (n=14-20/group). Sham controls were treated with vehicle (Sham-Veh; n=17). Areal and volumetric BMD, urine NTx, and serum osteocalcin were measured at baseline and months 3, 6, 12, and 16. Double fluorochrome labels were injected prior to iliac and rib biopsies at month 6 and month 12, and prior to sacrifice at month 16. Histomorphometry was performed on these biopsies, the tibial diaphysis, the L2 vertebra, and the proximal femur. Strength of humeral cortical beams, femur diaphysis, femur neck, and trabecular cores of L5-L6 vertebrae was determined by destructive biomechanical testing. There was no evidence of woven bone, osteomalacia, or other bone histopathologic changes with OVX or with denosumab. OVX-Veh animals exhibited significantly greater bone remodeling at all skeletal sites relative to Sham-Veh controls. Both doses of denosumab markedly inhibited bone remodeling at all sites, including significant reductions in trabecular eroded surfaces (48-86% lower than OVX-Veh controls), cortical porosity (28-72% lower), and dynamic parameters of bone formation (81-100% lower). Decreased fluorochrome labeling with denosumab was related to reductions in cortical porosity and trabecular eroded surfaces, and regression analyses suggested that these reductions contributed to denosumab-related increments in BMD and bone strength. Denosumab-treated animals with the lowest levels of fluorescent labeling exhibited the greatest structural bone strength values at each site. Intracortical remodeling had no relationship with material properties including ultimate strength, elastic modulus or toughness (r(2)=0.00-0.01). These data suggest that remodeling inhibition with denosumab improved structural strength without altering material properties under these experimental conditions. Greater structural strength in the denosumab-treated animals can be primarily explained by the combined effects of increased trabecular and cortical bone mass, and reductions in trabecular eroded surfaces and cortical porosity.     

Relationships between quantitative histological measurements and noninvasive assessments of bone mass.

We performed a comprehensive analysis of the relationships between histologic indices in the iliac crest (cancellous bone volume, trabecular structural indices, cortical width, and core width) and bone density in the spine, hip, and wrist in 81 patients with various metabolic bone diseases including osteoporosis, osteomalacia, hyperparathyroidism, and Paget's disease. In the whole group, all of the histologic indices correlated significantly with bone mineral density (BMD) of the spine and the three regions of the hip (r = 0.28-0.73), with the exception of cortical width which correlated with the hip but not the spine (r = 0.21). There was no relationship between the histologic variables and either the distal or proximal radius. When the osteoporotic subgroup was considered separately, the relationships between BMD and both cancellous bone volume and the structural indices (trabecular number, separation, and thickness) were lost. In contrast, cortical width correlated more strongly with both spine and hip BMD. The relationship between core width and the spine was lost but persisted in the hip region. In female osteoporotic patients alone, only cortical width remained significantly correlated with spine or hip BMD. We conclude that the relationships between bone densities in the axial and peripheral regions and histomorphometric variables in iliac crest are not constant. In addition, cancellous bone volume and the trabecular structural indices relate well to noninvasive axial BMD measurements only in a heterogenous group with a large variance in both parameters. In the more homogeneous group with osteoporosis, cortical width appears to be a more powerful predictor of BMD at the important sites of osteoporotic fracture.     

Age-dependent morphometric alterations in the distal femora of male and female rats.

Morphologic parameters, bone area, bone-to-bone + marrow ratio, periosteal-to-periosteal + endocortical surface ratio, mean trabecular thickness, and surface-to-volume ratio were studied in the epiphysis and metaphysis of the distal femora of male and female rats (Heiligenberg strain) between birth and the end of the lifespan. With increasing age, bone area, bone-to-bone + marrow ratio, and mean trabecular thickness increases, whereas periosteal-to-periosteal + endocortical surface ratio and surface-to-volume ratio decreases in both parts of bone during the first 150 days. Afterwards, periosteal-to-periosteal + endocortical surface ratio, mean trabecular thickness, and surface-to-volume ratio remain constant, whereas the bone area and the bone-to-bone + marrow ratio decrease. Modeling data were measured by use of the vital labeling technique with calcein. From the stained bone area, the bone formation, the bone resorption, and the periosteal mineral apposition rates have been calculated. The bone formation rate, about 13,000%/year in the metaphysis and 2,000%/year in the epiphysis, respectively, is greatest after birth and decreases continuously with increasing age to 3.5%/year for both bone regions. During the first 150 days the bone resorption rate is lower than the bone formation rate, leading to an increase in bone area, but afterwards it is higher so that the area decreases. Likewise the periosteal mineral apposition rate is greater in the metaphysis (24 microns/day at day 50) than in the epiphysis (14 microns/day at day 50), but after 700 days it is comparable for both bone regions (0.07 microns/day). The absolute values of body weight, femur length, and bone area of epiphysis and metaphysis are greater in male rats; only the mean trabecular thickness and the periosteal mineral apposition rate are comparable in both sexes. The relative values of bone-to-bone + marrow ratio, periosteal-to-periosteal + endocortical surface ratio, bone formation rate, and bone resorption rate are comparable for both sexes.     

Low-level accelerations applied in the absence of weight bearing can enhance trabecular bone formation.

High-frequency whole body vibrations can be osteogenic, but their efficacy appears limited to skeletal segments that are weight bearing and thus subject to the induced load. To determine the anabolic component of this signal, we investigated whether low-level oscillatory displacements, in the absence of weight bearing, are anabolic to skeletal tissue. A loading apparatus, developed to shake specific segments of the murine skeleton without the direct application of deformations to the tissue, was used to subject the left tibia of eight anesthesized adult female C57BL/6J mice to small (0.3 g or 0.6 g) 45 Hz sinusoidal accelerations for 10 min/day, while the right tibia served as an internal control. Video and strain analysis revealed that motions of the apparatus and tibia were well coupled, inducing dynamic cortical deformations of less than three microstrain. After 3 weeks, trabecular metaphyseal bone formation rates and the percentage of mineralizing surfaces (MS/BS) were 88% and 64% greater (p < 0.05) in tibiae accelerated at 0.3 g than in their contralateral controls. At 0.6 g, bone formation rates and mineral apposition rates were 66% and 22% greater (p < 0.05) in accelerated tibiae. Changes in bone morphology were evident only in the epiphysis, where stimulated tibiae displayed significantly greater cortical area (+8%) and thickness (+8%). These results suggest that tiny acceleratory motions--independent of direct loading of the matrix--can influence bone formation and bone morphology. If confirmed by clinical studies, the unique nature of the signal may ultimately facilitate the stimulation of skeletal regions that are prone to osteoporosis even in patients that are suffering from confinement to wheelchairs, bed rest, or space travel.     

Stainable aluminum and not aluminum content reflects bone histology in dialyzed patients

Quantitative evaluation of stainable bone aluminum and measurement of bone aluminum content were done in 55 patients on chronic maintenance dialysis. All patients underwent bone biopsies. Histomorphometry of static and dynamic parameters of bone structure, bone formation and resorption, and quantitation of stainable bone aluminum at the osteoid-bone interface were performed. In addition, bone aluminum content was measured by atomic absorption spectrophotometry. Bone aluminum content was elevated in all patients (81 +/- 9.6 vs. 18 +/- 6 micrograms/g dry wt) and stainable aluminum was found in 47% of them. All patients with predominant low-turnover osteomalacia or adynamic bone disease displayed stainable bone aluminum. In contrast, stainable bone aluminum was not present in individuals with predominant-hyperparathyroid bone disease. Patients with stainable aluminum had lower bone mass (P less than 0.05), higher volume and surface of lamellar osteoid (P less than 0.01), less volume and surface of woven osteoid (P less than 0.05 and P less than 0.01), lower osteoblastic and osteoclastic indices (P less than 0.01), less doubly labelled osteoid seams, lower mineral apposition rate and lower bone formation rates (P less than 0.05 to P less than 0.01). Stainable aluminum correlated with volume of lamellar osteoid and cellular parameters of bone formation and resorption, mineral apposition rate, and bone formation rates (P less than 0.05 to P less than 0.001). In contrast, bone aluminum content correlated with volume of lamellar osteoid only (P less than 0.001). These findings indicate that stainable aluminum at the mineralization front and not aluminum content of bone reflects the histopathologic changes found in bone of dialyzed patients.     

Human lactation: forearm trabecular bone loss, increased bone turnover, and renal conservation of calcium and inorganic phosphate with recovery of bone mass following weaning

The calcium (Ca) metabolism of established human lactation was studied in 40 adult women (mean age 32.4 years) who had been breast-feeding for 6 months (Lac) and in 40 age-matched controls (Con) using fasting urine and blood biochemistry and forearm single-photon bone mineral densitometry (BMD). Serial studies were performed up to 6 months after weaning in Lac women and repeated once in Con women. During lactation the significant findings were (1) a selective reduction (7.1%, P less than 0.03) in BMD at the ultradistal site containing 60% trabecular bone, but not at two more proximal, chiefly cortical bone sites; (2) increased bone turnover affecting bone resorption [fasting hydroxyproline excretion, Lac 2.22 +/- 0.12 mumol/liter GF (mean +/- SEM), Con 1.19 +/- 0.04, P less than 0.001] and affecting bone formation (plasma alkaline phosphatase, Lac 81.9 +/- 2.5 IU/liter, Con 53.5 +/- 2.7, P less than 0.001, and serum osteocalcin, Lac 14.0 +/- 0.7 microgram/liter, Con 7.3 +/- 0.4, P less than 0.001); and (3) renal conservation in the fasting state of both Ca and inorganic phosphate (Pi) with a resultant moderate increase in plasma Pi but not in plasma Ca (total or ionized). There were no differences between the groups in serum parathyroid hormone (PTH, intact and midmolecule assays), 25-hydroxy- and 1,25-dihydroxyvitamin D, nephrogenous cyclic AMP production, or plasma creatinine.(ABSTRACT TRUNCATED AT 250 WORDS)