Unloading-induced Bone Loss Research Articles

Unloading Induces Osteoblastic Cell Suppression and Osteoclastic Cell Activation to Lead to Bone Loss via Sympathetic Nervous System

Osteoporosis is one of the major health problems in our modern world. Especially, disuse (unloading) osteoporosis occurs commonly in bedridden patients, a population that is rapidly increasing due to aging-associated diseases. However, the mechanisms underlying such unloading-induced pathological bone loss have not yet been fully understood. Since sympathetic nervous system could control bone mass, we examined whether unloading-induced bone loss is controlled by sympathetic nervous tone. Treatment with beta-blocker, propranolol, suppressed the unloading-induced reduction in bone mass. Conversely, beta-agonist, isoproterenol, reduced bone mass in loaded mice, and under such conditions, unloading no longer further reduced bone mass. Analyses on the cellular bases indicated that unloading-induced reduction in the levels of osteoblastic cell activities, including mineral apposition rate, mineralizing surface, and bone formation rate, was suppressed by propranolol treatment and that isoproterenol-induced reduction in these levels of bone formation parameters was no longer suppressed by unloading. Unloading-induced reduction in the levels of mineralized nodule formation in bone marrow cell cultures was suppressed by propranolol treatment in vivo. In addition, loss of a half-dosage in the dopamine beta-hydroxylase gene suppressed the unloading-induced bone loss and reduction in mineralized nodule formation. Unloading-induced increase in the levels of osteoclastic activities such as osteoclast number and surface as well as urinary deoxypyridinoline was all suppressed by the treatment with propranolol. These observations indicated that sympathetic nervous tone mediates unloading-induced bone loss through suppression of bone formation by osteoblasts and enhancement of resorption by osteoclasts.

Can Albuterol Help Resistance Exercise Attenuate Unloading-Induced Bone Loss?

Hind-limb-suspended rats incur attenuated bone loss with beta(2)-agonists, and humans note similar changes with concurrent resistance exercise. To examine if the beta(2)-agonist albuterol helps resistance exercise reduce unloading-induced bone loss, human subjects performed 40 days of unilateral limb suspension with their left legs, otherwise refraining from normal ambulatory activity. While performing left leg strength training 3 days.week(-1), subjects received a concurrent placebo or albuterol (16 mg.day(-1)) treatment. Left leg muscle and bone changes were analyzed with 2 x 2 analyses of covariance (ANCOVAs). Mechanical loading values were calculated from workouts and compared using a 2 x 5 analysis of variance (ANOVA) and a Tukey post hoc test. The resistance exercise-albuterol assignment evoked significant (p < 0.05) left leg bone mineral content (BMC) gains (+2.24%) after 40 days. During the final unloading days, the resistance exercise-placebo group's mechanical loading data declined (-13.91%) significantly (p < 0.05) versus initial values. A resistance exercise-albuterol assignment likely increased BMC by maintaining the mechanical loading stimulus.

Klotho-deficient mice are resistant to bone loss induced by unloading due to sciatic neurectomy.

Unloading induces bone loss as seen in experimental animals as well as in space flight or in bed-ridden conditions; however, the mechanisms involved in this phenomenon are not fully understood. Klotho mutant mice exhibit osteopetrosis in the metaphyseal regions indicating that the klotho gene product is involved in the regulation of bone metabolism. To examine whether the klotho gene product is involved in the unloading-induced bone loss, the response of the osteopetrotic cancellous bones in these mice was investigated. Sciatic nerve resection was conducted using klotho mutant (kl/kl) and control heterozygous mice (+/kl) and its effect on bone was examined by micro-computed tomography (microCT). As reported previously for wild-type mice (+/+), about 30% bone loss was induced in heterozygous mice (+/kl) by unloading due to neurectomy within 30 days of the surgery. By contrast, kl/kl mice were resistant against bone loss induced by unloading after neurectomy. Unloading due to neurectomy also induced a small but significant bone loss in the cortical bone of the mid-shaft of the femur in the heterozygous mice; no reduction in the cortical bone was observed in kl/kl mice. These results indicate that klotho mutant mice are resistant against bone loss induced by unloading due to neurectomy in both cortical and trabecular bone and indicate that klotho is one of the molecules involved in the loss of bone by unloading.

Bone remodeling and plasma bone markers in pigs fed calcium deficient diets

Bone is sensitive to the removal of mechanical loading and the severity of unloading-induced bone loss may be influenced by an individual's genotype, gender, and the specific anatomical region. Whether these factors influence bone's mechanosensitivity directly or indirectly through differences in phenotypic baseline bone morphology and cellular activity is unknown. Here, we examined whether indices of baseline bone morphology and cellular activity are associated with the gender- and site-specific susceptibility of bone to unloading. Adult mice (4 months old, BALB/cByJ × C3H/HeJ) were assigned to one of six groups: male and female baseline controls (n = 20 each), age-matched controls (n = 10 each), or disuse (n = 11 males, n = 12 females). All baseline controls were sacrificed (0 day) to establish baseline bone morphology with micro-computed tomography (n = 10 each gender) or baseline cellular activities using histomorphometry and tartrate-resistant acid phosphatase staining (n = 10 each gender). Age-matched control and disuse mice were sacrificed (21 days) to determine disuse-induced bone loss by micro-computed tomography. Following 21 days of unloading, trabecular bone loss in the distal femur and proximal tibia was, on average, 3-fold greater in the metaphyses than in the epiphyses and 2-fold greater in females than in males. Disuse-induced changes in cortical bone were 2-fold smaller than trabecular bone losses and were more apparent in females (5 of 6 regions) than in males (1 of 6 regions). Bone loss was inversely related to baseline bone volume fraction (R2 = 0.51 for females and 0.43 for males) and directly related to baseline bone surface to volume ratio (R2 = 0.69 for females and 0.60 for males). Additionally, trabecular bone loss was correlated with baseline mineral apposition rates and osteoclast surface to bone surface ratios (R2 = 0.86 and 0.46, respectively, genders combined). These data demonstrate that baseline bone morphology and cellular activity modulate bone loss and that, independent of gender, anatomical regions with low bone quantity, high surface-to-volume ratios, and high levels of osteoblastic and osteoclastic activity are particularly susceptible to disuse.