Estrogen decreases bone formation by decreasing remodeling, but formation is decreased less than resorption and bone mass increases.

Data and modified from Raisz, L. G. (1999). Physiology and pathophysiology of bone remodeling. Clinical chemistry, 45 (8B): 1353-1358.

**Table 1.** Local and systemic regulation of bone remodeling.

PTH is a stimulator of bone resorption and 1,25-Dihydroxy vitamin D has its greatest effect on intestinal calcium and phosphate absorption, but it may also have direct effects on bone and other tissues. It is probably critical for the differentiation of both osteoblasts and osteoclasts and can stimulate bone resorption and formation under some experimental conditions. A third hormone, calcitonin (Table 1), in contrast to PTH and 1,25(OH)2 D3, both of which increase calcium release from the mineralized matrix, calcitonin is an inhibitor of osteoclast activity. It is a potent inhibitor of bone resorption and is used clinically in the treatment of bone diseases. Other systemic hormones are keys in regulating bone remodeling, such as: Growth hormone acting through both systemic and local insulin-like growth factor (IGF) production, can stimulate bone formation and resorption. Glucocorticoids are necessary for bone cell differ‐ entiation during development. Indirect effects of glucocorticoids on calcium absorption and sex hormone production may, however, increase bone resorption (Table 1). O the other hand, probably the most important systemic hormone in maintaining normal bone turnover is estrogen. Estrogen deficiency leads to an increase in bone remodeling in which resorption overcome formation and bone mass decreases (Table 1). The increase in bone remodeling and in bone resorption in the estrogen deficient state is associated with an increase in bone formation at the tissue level [51]. Therefore, sex steroid deficiency is associated with a defect in bone formation. Based on the available evidence, there are currently at least three key mechanisms by which estrogen deficiency may lead to a relative deficit in bone formation through direct effects on osteoblasts: increased apoptosis, increased oxidative stress, and an increase in NF-kB activity (Figure 3). In addition, estrogen inhibits the activation of bone remodeling, and this effect is most likely mediated via the osteocyte [52].

### **4.2. Parathyroid hormone (TH) and PTHrP signals**

increased bone resorption may result in bone loss. Therefore, the stimulation of bone formation may be another important factor for the prevention and treatment of bone loss (Figure 2).

The process of bone remodeling is essential for adult bone homeostasis. This control involves a complex mechanism compound by numerous local and systemic factors, and their expression and release is controlled finely. The main factor that affects normal bone remodeling is the regulation of osteoblasts and osteoclasts. Local and systemic factors can affect bone remodeling by directly or indirectly targeting mature cells and their respective progenitor cells. The metabolic functions of the bone are mediated by two major calcium-regulating hormones,

> **Bone reabsorption (osteoclast activity)**

Parathyroid hormone (PTH) ↑ ↑\* 1,25(OH)2 Vitamin D ↑ ↑\* Calcitonin ↓ ? Estrogen ↓ ↓#

Growth hormone/IGF ↑ ↑ Thyroid hormone ↑ ↑
