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Local immobilization is a good model for studying disuse-induced bone loss and to appreciate the effects of drugs, especially preventive action of antiresorptive therapy. In fact, increased osteoclastic activity is the main point of such a bone loss. The effect of salmon calcitonin was investigated on immobilization-induced osteoporosis in the sheep. Twenty-four nonovariectomized, adult, female, Welsh mountain sheep were submitted, by an external fixator procedure, to hock joint immobilization from the tibia to the the metatarsus for 12 weeks. The sheep were randomized into two groups receiving either an injection of placebo or salmon calcitonin (100 IU) three times per week, for 12 weeks. Histomorphometric analysis was performed on pre- and posttherapeutic transiliac bone biopsies, and on immobilized (left) and nonimmobilized calcanei removed after sacrifice. Results showed a 29% significant decrease of cancellous bone volume in the placebo group due to a significant reduced trabecular thickness when we compared immobilized versus nonimmobilized calcaneus. This structural adaptation appeared to be the consequence of an overall increased bone turnover. In the calcitonin group, same changes were observed, with a 23% reduction of bone mass in the immobilized calcaneus. By comparing calcitonin with placebo groups in both left and right calcanei, no difference was found. On the other hand, a significant increase of mineralization parameters in the iliac crest was only observed in the calcitonin group. In conclusion, salmon calcitonin, at a dose of 100 IU/day three times a week, was ineffective in preventing local disuse osteoporosis in this sheep model. [ABSTRACT FROM AUTHOR]

Adaptive changes in bone modeling in response to noninvasive, cyclic axial loading of the rat ulna were compared with those using 4-point bending of the tibia. Twenty cycles daily of 4-point bending for 10 days were applied to rat tibiae through loading points 23 and 11 mm apart. Control bones received nonbending loads through loading points 11 mm apart. As woven bone was produced in both situations, any strain-related response was confounded by the response to direct periosteal pressure. Four-point bending is not, therefore, an ideal mode of loading for the investigation of strain-related adaptive modeling. The ulna's adaptive response to daily axial loading over 9 days was investigated in 30 rats. Groups 1-3 were loaded for 1200 cycles: Group 1 at 10 Hz and 20 N, Group 2 at 10 Hz and 15 N, and Group 3 at 20 Hz and 15 N. Groups 4 and 5 received 12,000 cycles of 20 N and 15 N at 10 Hz. Groups 1 and 4 showed a similar amount of new bone formation. Group 5 showed the same pattern of response but in reduced amount. The responses in Groups 2 and 3 were either small or absent. Strains were measured with single-element, miniature strain gauges bonded around the circumference of dissected bones. The 20 N loading induced peak strains of 3500-4500 mustrain. The width of the periosteal new bone response was proportional to the longitudinal strain at each point around the bone's circumference. It appears that when a bone is loaded in a normal strain distribution, an osteogenic response occurs when peak physiological strains are exceeded. In this situation the amount of new bone formed at each location is proportional to the local surface strain. Cycle numbers between 1200 and 12,000, and cycle frequencies between 10 and 20 Hz have no effect on the bone's adaptive response. [ABSTRACT FROM AUTHOR]

Cyclic mechanical loading in vivo that leads to new bone formation is also associated in osteocytes and surface bone cells with almost immediate increases in G6PD activity, and later increases in RNA production. Both these early, loading-related, responses can be reproduced in organ culture of adult cancellous bone, and both are abolished by the presence of indomethacin in the culture medium at the time of loading. The implication that prostaglandins (PGs) are involved in the control of loading-related osteogenesis is supported by increases in prostacyclin (PGI2) and PGE2 release from cores of cancellous bone during loading. In the experiments reported here, PGE2 and PGI2 were added exogenously (10(-6) M) to perfusable cores of adult canine cancellous bone to determine whether they would simulate the loading-related responses in G6PD activity and RNA synthesis. PGE2 increased G6PD activity in surface cells and osteocytes within 8 minutes but had no effect on [3H]-uridine incorporation at 6 hours. PGI2 stimulated both G6PD activity and [3H]-uridine incorporation equally in osteocytes and surface cells. Neither PG produced any significant change in medium concentrations of IGF-I, and PGE2 had no effect on IGF-II. In contrast PGI2 elevated the medium concentration of IGF-II threefold. IGF-I and IGF-II were localized immunocytochemically to osteocytes and surface cells in both treated and untreated cores. Prostacyclin, but not PGE2, appears to imitate the early loading-related increases in G6PD activity and RNA synthesis in bone cells in situ. Prostacyclin, but not PGE2, also stimulates the early release of IGF-II. [ABSTRACT FROM AUTHOR]

Pairs of 17-day embryonic chick tibiotarsi were removed and maintained in organ culture. One of each pair was subjected to a single 20-minute period of intermittent loading at 0.4 Hz, producing peak longitudinal compressive strains of 650 microstrain (mu epsilon). In the 18-hour culture period following loading, alkaline phosphatase levels in the osteoblasts of the loaded tibiotarsi were maintained whereas in controls they declined. In situ hybridization using a collagen type I cRNA riboprobe showed a substantial increase in expression of mRNA for collagen type I in the periosteal tissue of bones that were cultured for 18 hours after loading compared with that in similarly cultured controls and bones cultured for 4 hours. These results demonstrate that appropriate loading of embryonic chick bones in organ culture elicits adaptive regulation of matrix synthesis as evidenced by increased expression of the gene for type I collagen and alkaline phosphatase activity. This model may be useful as it must contain all the obligatory steps between strain change in the matrix and modified osteogenic activity. [ABSTRACT FROM AUTHOR]

Previous studies of Alcian blue-induced birefringence in adult avian cortical bone showed that a short period of intermittent loading rapidly produces an increased level of orientation of proteoglycans within the bone tissue. In the absence of further loading, this persists for over 24 hours. We have proposed that this phenomenon could provide a means for "capturing" the effects of transient strains, and so provide a persistent, constantly updated strain-related influence on osteocyte populations related to the bones' averaged recent strain history, in effect, a "strain memory" in bone tissue. In our present study, we use the Alcian blue-induced birefringence technique to demonstrate that proteoglycan orientation also occurs after intermittent loading of both cortical and cancellous mammalian bone in vivo and in vitro. We also show that the change in birefringence is proportional to the magnitude of the applied strain, and that the reorientation occurs rapidly, reaching a maximal value after only 50 loading cycles. Examination of electron micrographs of bone tissue after staining with cupromeronic blue allows direct visualization and quantification of the change in proteoglycan orientation produced by loading. This shows that intermittent loading is associated with a realignment of the proteoglycan protein cores, bringing them some 5 degrees closer to the direction of collagen fibrils in the bone matrix. [ABSTRACT FROM AUTHOR]

The capacity of bone to organize and reorganize its structure in response to changing mechanical demands is well recognized. However, the mechanism by which the changing mechanical environment is detected, and the means by which this information is translated into a stimulus for structural modification, are not understood. A group of substances suggested to be involved in the initial transduction of strain information are the prostaglandins. In this experiment we used a single period of dynamic loading to stimulate an adaptive osteogenic response in vivo. Loading was performed in the presence and absence of indomethacin. Measurements of the periosteum 5 days after loading showed that the presence of indomethacin at the time of loading reduced the osteogenic response. Though consistent with the hypothesis that prostaglandins are involved in the initial transduction of tissue strain into a biochemical response, this result is not sufficient to demonstrate this conclusively because reduced prostaglandin levels during the 24 hours immediately after the period of loading may affect many other points in the cascade of events between strain transduction and adaptive new bone formation. Furthermore, indomethacin at the relatively high levels we used (40 mg/kg) may have effects other than those on prostaglandin synthesis. [ABSTRACT FROM AUTHOR]

Both ulnas of skeletally mature roosters (Gallus domesticus) were deprived of functional load bearing by proximal and distal submetaphyseal osteotomies. Twenty-four hours later the animals were injected with 1.5 mCi of 3H-uridine and the ulna on one side was subjected to a single period of a cyclical load engendering physiological strain levels at 1 Hz for 6 min. Twenty-four hours after loading the animals were killed. Autoradiographic examination of comparable regions of cortex in sections from the bone's midshafts showed that in the loaded bones, 72 +/- 2.7% of osteocytes were labeled compared with 12 +/- 3.5% in the corresponding areas of their contralateral nonloaded pair (P less than 0.001). The number of grains per labeled osteocyte was also higher in the loaded side (6 +/- 0.5 compared with 4 +/- 0.5, P less than 0.01). There was no obvious correlation between the longitudinal strain distribution during artificial loading and the distribution of labeled osteocytes throughout the bone cross-section. However, previous long-term experiments using a similar loading preparation had consistently shown the site of most periosteal new bone formation to also not be directly related to the local strain magnitude. Perhaps it is significant that the greatest percentage of labeled cells were found in the cortex where the long-term experiments had shown most new bone formation to subsequently occur. [ABSTRACT FROM AUTHOR]

An animal model was used to examine the use of noninvasive transmission ultrasound to measure changes in bone mass which occur following disuse. Unilateral achilles tenectomy was performed on the left leg of eight adult sheep. Following a 12-week period of nonweight bearing, presacrifice transmission ultrasound measurements were taken across the calcanei of the intact and the experimental limbs and compared with those values taken postoperatively. Following specimen harvest, cross-sectional areas of the bones were quantified by microradiography and stereology, and compared with the in vivo ultrasound measurements. There was an average of 8.6% less total bone area, and 18.0% less trabecular volume fraction in the experimental nonweight-bearing limbs as compared with control intact calcanei. The difference in bone mass was associated with a 9.0% decrease in the velocity of sound from the postoperative to the presacrifice ultrasound measurements taken from the experimental calcanei, and a 2.3% increase in the control calcanei. The velocity of sound was found by the Student's t test to be a highly reliable discriminator between the experimental and control limbs. [ABSTRACT FROM AUTHOR]

Changes in the midshaft cross-sectional area of the ulna were measured in egg-laying turkeys on a diet insufficient in calcium. Left:right comparisons were used to assess the bone loss over a six-week period due to 1) calcium insufficiency, 2) calcium insufficiency plus disuse, and 3) calcium insufficiency and disuse interrupted by a short daily period of intermittent loading applied from an external device. Calcium insufficiency alone in the intact ulna resulted in a 15% reduction in cross-sectional area. In the functionally deprived bones this loss was increased to 32%. In bones where the disuse was interrupted by a single short daily period of loading, the degree of bone loss was significantly modified (P less than 0.006) to 25%. No significant difference in the modulating effect of loading was achieved by varying the peak strain from 0.0015 to 0.003, the strain rate from 0.01 to 0.05, or the duration of the single loading period from 100 sec per day to 25 minutes. All the loading regimes employed had been demonstrated to be osteogenic in mature male birds on a diet sufficient in calcium. [ABSTRACT FROM AUTHOR]

The in vivo remodeling behavior within a bone protected from natural loading was modified over an 8-week period by daily application of 100 consecutive 1 Hz load cycles engendering strains within the bone tissue of physiological rate and magnitude. This load regime resulted in a graded dose:response relationship between the peak strain magnitude and change in the mass of bone tissue present. Peak longitudinal strains below 0.001 were associated with bone loss which was achieved by increased remodeling activity, endosteal resorption, and increased intra-cortical porosis. Peak strains above 0.001 were associated with little change in intra-cortical remodeling activity but substantial periosteal and endosteal new bone formation. [ABSTRACT FROM AUTHOR]

Mechanical function has always been acknowledged to have a significant, continuing but hitherto unquantified influence on bone remodeling. The structural objective of this relationship is presumably to ensure that, at each location throughout the skeleton, there is sufficient bone tissue, appropriately placed, to withstand functional load-bearing without damage. The architectural modifications necessary to achieve and maintain this structural competence are made by the coordinated remodeling activity of populations of osteoblasts and osteoclasts. The specific structure-function objectives at each location remain undefined, as are the mechanisms by which tissue loading is transduced into cellular control. The remodeling responses following a variety of experimental alterations in bones' strain environment are presented. Their significance to the process of remodeling control is discussed, and a scheme for the interaction of mechanical and hormonal influences proposed. [ABSTRACT FROM AUTHOR]