Estrogen regulates the rate of bone turnover but bone balance in ovariectomized rats is modulated by prevailing mechanical strain

Abstract

Estrogen deficiency induced bone loss is associated with increased bone turnover in rats and humans. The respective roles of increased bone turnover and altered balance between bone formation and bone resorption in mediating estrogen deficiency-induced cancellous bone loss was investigated in ovariectomized rats. Ovariectomy resulted in increased bone turnover in the distal femur. However, cancellous bone was preferentially lost in the metaphysis, a site that normally experiences low strain energy. No bone loss was observed in the epiphysis, a site experiencing higher strain energy. The role of mechanical strain in maintaining bone balance was investigated by altering the strain history. Mechanical strain was increased and decreased in long bones of ovariectomized rats by treadmill exercise and functional unloading, respectively. Functional unloading was achieved during orbital spaceflight and following unilateral sciatic neurotomy. Increasing mechanical loading reduced bone loss in the metaphysis. In contrast, decreasing loading accentuated bone loss in the metaphysis and resulted in bone loss in the epiphysis. Finally, administration of estrogen to ovariectomized rats reduced bone loss in the unloaded and prevented loss in the loaded limb following unilateral sciatic neurotomy in part by reducing indices of bone turnover. These results suggest that estrogen regulates the rate of bone turnover, but the overall balance between bone formation and bone resorption is influenced by prevailing levels of mechanical strain.

Figure 1

(A) Comparative effects of 1 month of gonadal insufficiency following OVX on cancellous bone volume in the proximal tibia. Representative microtomographic images from an ovary-intact (Left) and OVX (Right) rat showing greatly decreased cancellous bone in the metaphysis (large arrow) but little change in the epiphysis (small arrow) following OVX. (B) Comparative effects of 11.5 months of gonadal insufficiency following OVX on cancellous bone volume in the distal femur. Representative microtomographic images from an ovary-intact (Left) and OVX (Right) showing little change in cancellous bone in the epiphysis even though there was dramatic loss from the metaphysis (Fig. 2).

Figure 2

Comparative effects of 11.5 months of gonadal insufficiency following OVX on cancellous bone volume in the distal femur. Quantitative histomorphometry revealed that the metaphysis undergoes a significant decrease in cancellous bone area whereas there was no change in the epiphysis. Values are mean ± SE; n = 6.

Figure 3

Data for 11.5 months of gonadal insufficiency result in greatly elevated indices of bone turnover in the distal femur epiphysis. The results demonstrate that increased bone turnover does not in-and-of-itself result in bone loss. Values are mean ± SE; n = 4 for steady-state mRNA levels and n = 6 for histomorphometric values.

Figure 4

The strain energy distribution within the distal femur predicted by a two-dimensional finite element model. Lighter areas represent high strain energy whereas darker areas represent low strain energy. The cancellous bone loss which follows OVX occurs predominantly at sites subjected to low strain energies.

Figure 5

Decreased weight bearing (spaceflight) results in cancellous bone loss from the proximal tibial epiphysis of OVX rats. Increased weight bearing (treadmill exercise) antagonizes cancellous bone loss at the proximal tibial metaphysis. Values are mean ± SE; n = 8–10; P < 0.05 compared with either baseline or sham control.

Figure 6

Comparative effects of weight bearing and estrogen on cancellous bone volume in OVX rats. Rats were ovariectomized 7.5 weeks prior to USN to establish bone loss in the tibial metaphysis. Following OVX, there was no significant change in bone area in the epiphysis whereas bone area was reduced in the metaphysis (P < 0.05) at all time points. In contrast, USN resulted in bone loss in the epiphysis and further bone loss in the metaphysis. Half of the rats were implanted with subcutaneous implants designed to deliver 17β-estradiol at a constant rate totaling 0.2 mg during a 6-week interval (+E). Estrogen treatment prevented bone loss following USN in the epiphysis and prevented further bone loss in the metaphysis. Values are mean ± SE; n = 10. ∗, P < 0.05; ∗∗, P < 0.01 compared with baseline controls (time 0). Figure data points without error bars are larger than ± SE.