**5. Bone metabolism system**

The main problem of the skeletal system is bone calcium (Ca2+) loss during microgravity. The bone becomes fragile during microgravity exposure, which can harm an astronaut or cosmonaut even after returning to Earth. Moreover, the risk of renal stones is high during long-term missions due to hypercalcemia [39].

Ca2+ plays an essential role in bone structure, contraction of skeletal and cardiac muscles, neural transmission, blood coagulation, cell permeability, and hormonal signaling. The serum Ca2+ level is well maintained at 8.4–10.2 mg/dL. Ca2+ is absorbed from the small intestine (300 mg/day), into the blood, deposited in the bone (500 mg/day), and excreted from the kidneys (150 mg/day) or into feces.

In this section, the influences of gravity on bone structure and of hormones on bone formation and absorption are described.

#### **5.1 Bone development and restructuring**

Gravity influences the long bones of the lower extremities, e.g., the femur, tibia, calcaneus, and vertebrae, which support the body in the upright position. Bone tissue contains osteocytes, which develop from osteoblasts, and are changed into osteoclasts by the action of RANKL (also called osteoclast differentiation factor, short for receptor activation of NF-kappa B ligand).

Osteoblasts and osteoclasts are functionally closely related, as is the balance between bone formation and bone resorption. Thus, insufficient bone formation compared with bone resorption observed in spaceflight reduces the bone mass and bone strength, leading to fractures.

Two hormones, calcitonin and parathormone (PTH), and vitamin D play an essential role in Ca2+ metabolism. Calcitonin is secreted from C cells of the thyroid gland. The secretion of calcitonin is promoted by an increase in the blood calcium concentration and is suppressed by the decrease in the serum calcium level. Calcitonin acts on the calcitonin receptor in osteoclasts to suppress the release of Ca2+ from the bone and promotes the deposition of calcium and phosphate on the bone. Calcitonin also promotes the excretion of calcium and phosphate into the urine. As a result, the serum level of Ca2+ decreases.

PTH is secreted from the parathyroid gland, increasing the release of Ca2+ from bone. PTH binds to osteoblasts to increase the expression of RANKL and inhibits their secretion of osteoprotegerin (OPG), which competitively binds to RANKL, preventing RANKL from interacting with RANK (receptor for RANKL). The binding of RANKL stimulates osteoclast precursors to fuse, forming new osteoclasts. As a result, PTH increases bone resorption, thereby increasing the serum Ca2+ level.

Vitamin D (25-hydroxycholecalciferol) acts on the parathyroid gland and suppresses the synthesis and secretion of PTH. The intestinal tract promotes the absorption of calcium and phosphorus. Vitamin D is essential for bone formation, but its direct action on bone formation remains unclear. It is also necessary for the formation of osteoclasts, affects the bone action of PTH, and promotes bone resorption itself at a high concentration. In the kidney, vitamin D increases Ca2+ reabsorption in the distal tubule and promotes the Ca2+ reabsorption action of PTH.

#### **5.2 Effects of microgravity on bone metabolism**

The main factor of bone metabolism is mechanical impact. Gravity creates weight and is responsible for the pressure exerted on a large part of the skeleton, resulting in a mechanical impact on bones. These gravitational impacts provide mechanical constraints on the femurs, tibias, calcaneus, and vertebrae. Thus, decalcification and bone loss are observed as the result of bone resorption, and the disappearance of gravity from the body axis components induces bone loss and resultant osteoporosis [2, 40].

#### **5.3 Effects of spaceflight on bone metabolism**

In microgravity conditions, decalcification was observed in 12 of the astronauts on the Gemini and Apollo 7 and 8 flights in 1969 [8]. Based on bone density measured using X-rays, the bone Ca2+ loss was 3.2%.

The bone mineral density was measured before and after the Mir program. The changes were as follows: +0.6% in the skull, +0.1% in the arm, −1.07% in the spine, −1.35% in the pelvis, −1.16% in the femoral neck, −1.58% in the trochanter major, −1.25% in the tibia, and −1.50% in the calcaneus per month, with comparable results from the ISS [41]. The most affected bones during spaceflight are weightbearing bones, e.g., the pelvis (os coxae), the trochanter major of the femur, the femoral neck, the tibia, and the calcaneus.

Mir studies using dual photonic densitometry demonstrated a mean decrease in bone mineral density of approximately 0.3%/month in the cortical bone and up to 0.9%/month in cancellous tibial bone. Decalcification only occurs in the weightbearing bones, and demineralization is correlated with mission duration. During spaceflight, hypercalcemia and hyperphosphatemia develop due to demineralization, and Ca2+ excretion into the urine increases before stabilization at around the 30th day of flight [42].

The National Aeronautics and Space Administration (NASA) of the United States documented a bone mineral loss rate/month of 1–2% during spaceflight

**23**

*Effects of Microgravity on Human Physiology DOI: http://dx.doi.org/10.5772/intechopen.90700*

influenced by the spaceflight duration.

density loss [42].

(https://science.nasa.gov/science-news/science-at-nasa/2001/ast01oct\_1), and bone density loss of 5–6% was reported in Apollo 15 crewmembers [43]. Bone loss is

Tail suspension studies on rats demonstrated that simulated microgravity reduces bone formation, alters the Ca2+ balance, and inhibits the proliferation and differentiation of osteoprogenitor cells [44]. Osteocytes can also be affected by unloading stimulus in a bioreactor, with high expression of inhibitors of bone

Osteoporosis can be irreversible. After returning to Earth without appropriate rehabilitation, the bone may be unable to return to normal activity under loads and may be weaker, easily inducing fractures. Reloading after a period of a week can ameliorate bone weakness, but even 2 weeks of bone restoration was not satisfactory. The length of spaceflight influences the bone density loss; however, another report stated that the bone loss at 1 month continued to increase after 6 months, suggesting that the length of spaceflight does not determine the bone

Wolff's law characterizes how the bone adapts to functionally withstand its mechanical environment [46]; however, several studies found that mechanical

Then what are the effects of mechanical impact on calcitonin? Calcitonin receptors were not observed on osteoblasts [52] but were present on osteoclasts [53] and osteocytes [54]. Calcitonin was reported to inhibit apoptosis of osteoblasts and osteocytes, demonstrating a potential indirect influence on bone formation. These data confirmed that mechanical impact is not directly related to bone formation. One notable property of PTH is that although chronic increases in PTH levels increase bone resorption, intermittent stimulation accelerates bone formation. PTH stimulates osteoclast formation by binding to PTH receptor 1 on stromal/osteoblastic cells and thereby increases the production of receptor activator of RANKL and macrophage colony-stimulating factor (M-CSF) and suppresses the RANKL decoy receptor osteoprotegerin. Moreover, PTH controls the production of osteoblasts through actions on osteocytes through Wnt signaling in osteoblastogenesis [55]. The action of osteocytes, which can directly sense a mechanical unloading stimulus, increased the expression of both inhibitors of bone formation (SOST/ sclerotin) and stimulators of bone resorption (RANKL) through Wnt signaling [45]. These results support the hypothesis that intermittent mechanical impacts induce osteocyte action, which inhibits bone formation and stimulates bone resorption, and that an intermittent increase in PTH controls the production of osteoblasts.

formation (sclerotin) and stimulators of bone resorption (RANKL) [45].

**5.4 Effects of mechanical impact on hormonal influence**

loading per se is not the direct stimulus for bone remodeling [47–51].

**5.5 Sympathetic alteration of bone metabolism during spaceflight**

exposed to long-term spaceflight will be discussed.

It has been reported that sympathetic neural traffic to bone inhibits the function of osteoblast and increases that of osteoclast, thus facilitating bone loss. Possible roles of the sympathetic nervous system in the mechanisms of bone loss in humans

Prolonged exposure to microgravity in space for 14 days increased sympathetic neural traffic in humans based on results from the Neurolab mission [14, 56–58], with comparable increases in noradrenaline spillover and clearance in space [14]. Concordant results were obtained during simulated microgravity, including dry immersion [28] or head-down bedrest [17]. In general, elderly people have a low bone density and high sympathetic neural traffic to muscles [59]. Our preliminary

### *Effects of Microgravity on Human Physiology DOI: http://dx.doi.org/10.5772/intechopen.90700*

*Beyond LEO - Human Health Issues for Deep Space Exploration*

urine. As a result, the serum level of Ca2+ decreases.

**5.2 Effects of microgravity on bone metabolism**

**5.3 Effects of spaceflight on bone metabolism**

sured using X-rays, the bone Ca2+ loss was 3.2%.

femoral neck, the tibia, and the calcaneus.

resultant osteoporosis [2, 40].

Two hormones, calcitonin and parathormone (PTH), and vitamin D play an essential role in Ca2+ metabolism. Calcitonin is secreted from C cells of the thyroid gland. The secretion of calcitonin is promoted by an increase in the blood calcium concentration and is suppressed by the decrease in the serum calcium level. Calcitonin acts on the calcitonin receptor in osteoclasts to suppress the release of Ca2+ from the bone and promotes the deposition of calcium and phosphate on the bone. Calcitonin also promotes the excretion of calcium and phosphate into the

PTH is secreted from the parathyroid gland, increasing the release of Ca2+ from bone. PTH binds to osteoblasts to increase the expression of RANKL and inhibits their secretion of osteoprotegerin (OPG), which competitively binds to RANKL, preventing RANKL from interacting with RANK (receptor for RANKL). The binding of RANKL stimulates osteoclast precursors to fuse, forming new osteoclasts. As a result, PTH increases bone resorption, thereby increasing the serum Ca2+ level. Vitamin D (25-hydroxycholecalciferol) acts on the parathyroid gland and suppresses the synthesis and secretion of PTH. The intestinal tract promotes the absorption of calcium and phosphorus. Vitamin D is essential for bone formation, but its direct action on bone formation remains unclear. It is also necessary for the formation of osteoclasts, affects the bone action of PTH, and promotes bone resorption itself at a high concentration. In the kidney, vitamin D increases Ca2+ reabsorption in the distal tubule and promotes the Ca2+ reabsorption action of PTH.

The main factor of bone metabolism is mechanical impact. Gravity creates weight and is responsible for the pressure exerted on a large part of the skeleton, resulting in a mechanical impact on bones. These gravitational impacts provide mechanical constraints on the femurs, tibias, calcaneus, and vertebrae. Thus, decalcification and bone loss are observed as the result of bone resorption, and the disappearance of gravity from the body axis components induces bone loss and

In microgravity conditions, decalcification was observed in 12 of the astronauts on the Gemini and Apollo 7 and 8 flights in 1969 [8]. Based on bone density mea-

The bone mineral density was measured before and after the Mir program. The changes were as follows: +0.6% in the skull, +0.1% in the arm, −1.07% in the spine, −1.35% in the pelvis, −1.16% in the femoral neck, −1.58% in the trochanter major, −1.25% in the tibia, and −1.50% in the calcaneus per month, with comparable results from the ISS [41]. The most affected bones during spaceflight are weightbearing bones, e.g., the pelvis (os coxae), the trochanter major of the femur, the

Mir studies using dual photonic densitometry demonstrated a mean decrease in bone mineral density of approximately 0.3%/month in the cortical bone and up to 0.9%/month in cancellous tibial bone. Decalcification only occurs in the weightbearing bones, and demineralization is correlated with mission duration. During spaceflight, hypercalcemia and hyperphosphatemia develop due to demineralization, and Ca2+ excretion into the urine increases before stabilization at around the

The National Aeronautics and Space Administration (NASA) of the United States documented a bone mineral loss rate/month of 1–2% during spaceflight

**22**

30th day of flight [42].

(https://science.nasa.gov/science-news/science-at-nasa/2001/ast01oct\_1), and bone density loss of 5–6% was reported in Apollo 15 crewmembers [43]. Bone loss is influenced by the spaceflight duration.

Tail suspension studies on rats demonstrated that simulated microgravity reduces bone formation, alters the Ca2+ balance, and inhibits the proliferation and differentiation of osteoprogenitor cells [44]. Osteocytes can also be affected by unloading stimulus in a bioreactor, with high expression of inhibitors of bone formation (sclerotin) and stimulators of bone resorption (RANKL) [45].

Osteoporosis can be irreversible. After returning to Earth without appropriate rehabilitation, the bone may be unable to return to normal activity under loads and may be weaker, easily inducing fractures. Reloading after a period of a week can ameliorate bone weakness, but even 2 weeks of bone restoration was not satisfactory. The length of spaceflight influences the bone density loss; however, another report stated that the bone loss at 1 month continued to increase after 6 months, suggesting that the length of spaceflight does not determine the bone density loss [42].

## **5.4 Effects of mechanical impact on hormonal influence**

Wolff's law characterizes how the bone adapts to functionally withstand its mechanical environment [46]; however, several studies found that mechanical loading per se is not the direct stimulus for bone remodeling [47–51].

Then what are the effects of mechanical impact on calcitonin? Calcitonin receptors were not observed on osteoblasts [52] but were present on osteoclasts [53] and osteocytes [54]. Calcitonin was reported to inhibit apoptosis of osteoblasts and osteocytes, demonstrating a potential indirect influence on bone formation. These data confirmed that mechanical impact is not directly related to bone formation.

One notable property of PTH is that although chronic increases in PTH levels increase bone resorption, intermittent stimulation accelerates bone formation. PTH stimulates osteoclast formation by binding to PTH receptor 1 on stromal/osteoblastic cells and thereby increases the production of receptor activator of RANKL and macrophage colony-stimulating factor (M-CSF) and suppresses the RANKL decoy receptor osteoprotegerin. Moreover, PTH controls the production of osteoblasts through actions on osteocytes through Wnt signaling in osteoblastogenesis [55].

The action of osteocytes, which can directly sense a mechanical unloading stimulus, increased the expression of both inhibitors of bone formation (SOST/ sclerotin) and stimulators of bone resorption (RANKL) through Wnt signaling [45]. These results support the hypothesis that intermittent mechanical impacts induce osteocyte action, which inhibits bone formation and stimulates bone resorption, and that an intermittent increase in PTH controls the production of osteoblasts.

### **5.5 Sympathetic alteration of bone metabolism during spaceflight**

It has been reported that sympathetic neural traffic to bone inhibits the function of osteoblast and increases that of osteoclast, thus facilitating bone loss. Possible roles of the sympathetic nervous system in the mechanisms of bone loss in humans exposed to long-term spaceflight will be discussed.

Prolonged exposure to microgravity in space for 14 days increased sympathetic neural traffic in humans based on results from the Neurolab mission [14, 56–58], with comparable increases in noradrenaline spillover and clearance in space [14]. Concordant results were obtained during simulated microgravity, including dry immersion [28] or head-down bedrest [17]. In general, elderly people have a low bone density and high sympathetic neural traffic to muscles [59]. Our preliminary study demonstrated that changes in sympathetic neural traffic to muscles after long-term bedrest of 20 days were significantly correlated with changes in the urinary secretion level of deoxypyridinoline [25, 60], which is used as a specific marker of bone resorption [61]. Based on these findings, exposure to prolonged microgravity may increase sympathetic neural traffic to the bone, which increases the noradrenaline level, thereby inhibiting osteogenesis and facilitating osteolysis through β-receptors to induce bone mineral loss.
