C role of vitamin d and Parathyroid Hormone in Microgravity-Induced Bone Loss by Michael Holick




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APPENDIX C


BONE AND CONNECTIVE TISSUE DISCIPLINE - SUPPORTING MATERIAL


Supplementary reports


C-1. Diet and Acid-Base Balance by Martin J. Fettman


C-2. Role of vitamin D and Parathyroid Hormone in Microgravity-Induced Bone Loss by Michael Holick


Report C-1

Diet and Acid-Base Balance

by Martin J. Fettman


Many factors in space flight may affect calcium metabolism and bone turnover, beyond the effects of microgravity ant changes in physical loading forces. Prior physical fitness may influence remodeling forces. Caloric balance influences the amount of energy available for anabolic processes, including bone matrix synthesis. Nitrogen balance reflects the quantity of amino acids retained which may be used for bone matrix synthesis. Finally, dietary calcium balance will affect the bone mineral density. It is important to note that "balance" is used to describe diet-related factors, rather than "intake". Many processes may affect "nutrient partitioning" so that alterations in balance diverge from those of dietary intake. In space flight, one example is that of dietary protein, nitrogen balance, and differential protein synthesis. Even during periods of decreased overall nitrogen balance, inflammatory cytokine release and hepatic acute phase protein synthesis may be increased, reflecting partitioning of amino acid metabolism (Stein et al, 1993; Stein and Schluter, 1994). Likewise, it is possible to modify mineral distribution through changes in dietary electrolyte composition and influences of acid-base metabolism.

Both respiratory acidosis (increased pCO2) and metabolic acidosis (decreased HCO3) have been shown to alter bone surface mineralization through physicochemical effects defined by the solubility product relationship between ionized calcium and phosphate (Bushinsky et al, 1992 Arnett et al, 1994). The precipitation of ionized calcium and phosphate is determined both by their concentrations and that of hydrogen ions ([Ca2+][Pi]/[H+] = K).

This principle has been exploited in veterinary medicine to manage particular animal disorders. For instance, dietary alkalization has been used to improve eggshell quality in poultry (Keshavarz, 1994). Dietary acidification has been used to improve bone calcium mobilization in dairy cows during their "dry" period just prior to parturition (Oetzel et al, 1991). This, in turn, protects against hypocalcemia developing subsequent to the onset of lactation. Likewise, both dietary acidification and alkalization affects the urinary pH and subsequent predisposition to urolithiasis in cats (Thumchai et al, 1996). Dietary acidification prevents struvite stone precipitation, but predisposes to calcium oxalate precipitation.

Metabolic acidosis has also been shown to alter bone remodeling through cellular effects. Decreased bicarbonate concentrations reduce osteoblast activity, and stimulate osteoclast activity, in addition to the physicochemical effects noted above (Krieger et al, 1992; Bushinsky et al, l995). There is controversy in the literature regarding the relative "potency" of respiratory vs. metabolic acidosis in altering bone mineral deposition (Sprague et al, l994; Arnett et al, 1994). Thus, we may have cause for concern about excursions in atmospheric pCO2 in the Space Station.

Acidosis has also been shown to alter the synthesis, release, and effectiveness of the calciotropic hormones (Ching et al, 1989). Acidosis increases the ionization of calcium, and increased ionized calcium concentrations in turn suppress the release of parathormone (PTH) from the parathyroid glands. On the other hand acidosis promotes the activity of PTH on bone mineral resorption. Acidosis also decreases PTH activity in the kidneys, resulting in decreased calcium reabsorption from the tubular fluid. Finally, acidosis decreases renal la-hydroxylase activity, thereby reducing the production of active calcitriol.

It has been hypothesized that the usual daily load of acid produced through metabolism might have similar effects on calcium metabolism and bone turnover, even in the absence of overt disturbances in acid-base balance. Daily oral intake of KHCO3 (but, not NaHCO3) to neutralize endogenous acid production significantly improves calcium balance, reduces bone resorption, and increases bone formation in healthy adult males (Lemann et al, l989) and in post-menopausal females (Sebastian et al, 1994). In addition, it is possible that in space flight, during periods of negative caloric and/or nitrogen balance, increased endogenous acid generated by accelerated rates of catabolism may also contribute to negative calcium balance.

Increased dietary sodium intake increases the filtered renal load of sodium for excretion. This, in turn, decreases renal tubular calcium reabsorption and increases urinary calcium excretion. Some have suggested that the sodium effect may be dependent on physical fitness and activity level (Navidi et al, 1995). Dietary sodium restriction has been shown to improve calcium balance in rats (Navidi et al, 1995) and in humans (Arnaud et al, 1996). but its effects on bone mineral density have not been confirmed.

Dietary sodium restriction may have other advantageous effects as well. In rats, sodium restriction increases renin-angiotensin-aldosterone responsiveness to subsequent salt repletion and volume expansion (Wilke et al, 1995). This may be useful for preconditioning astronauts prior to administration of volume expansion countermeasures for orthostasis.

Dietary alkalinization with potassium citrate, coupled with sodium restriction, has been shown to decrease the risk for urinary calcium oxalate precipitation (Goldfarb, l988). Thus, an additional benefit of dietary modification as described above might be reduced risk for urolithiasis.

Dietary alkalinization and potassium supplementation have been shown to increase nitrogen balance in some diseases (Gourgeon-Reybourn et al, 1991; Papadoyannakis et al, 1984). In additional benefit of dietary modification as described above might be moderation of reduced or negative nitrogen balance observed during some phases of space flight (Stein et al, 1993). This might also improve calcium balance as affected by endogenous acid produced through catabolism.

Quantitative dietary intake data for astronauts are limited, but indicate significant balances which may affect calcium metabolism and bone turnover. Caloric intake in 13 astronauts (8.76 +/- 2.26 Mj/day) appears to be significantly less than estimated energy expenditure (11.70+- 1.89 Mj/day) (Lane et al, 1997). This would be expected to adversely affect anabolic processes integral to bone remodeling, as well as net acid excretion and calcium balance. Sodium intake in 21 astronauts was 4116.6 + 883.1 mg/day (Lane, l996), well above that recommended to moderate urinary calcium excretion. This amount might also adversely affect humoral vascular responsiveness to salt and water loading in astronauts prior to return to Earth. Calcium intake (855.4 +- 220.0 mg/day) was very close to the recommended daily intake, and should not require major modification. It might be useful to calculate dietary cation-anion balance for comparison to urinary pH and titratable acid excretion in order to determine potential effects of supplemental dietary alkalinization on net acid excretion and calcium balance. While changes in blood gas parameters have not been observed in limited studies to date (Whitson, 1996), increased urinary calcium and sulfate losses (Whitson et al, 1993) may reflect increases in net acid excretion which could be moderated by dietary alkalinization.


Remaining questions include the following:


1. Are there thresholds for the dietary effects described above?


2. What are the changes in acid-base metabolism in microgravity? This should include not only overt changes in blood gas parameters, but also changes in urinary net acid elimination.


3. Is a lower sodium diet practicable for space flight This would include formulation of lower sodium foods, as well as concomitant modifications to maintain palatability and intake.


4. Is dietary buffer supplementation possible? This would require knowledge of the typical dietary cation-anion balance (potential dietary acidity) and effects modifications on palatability and intake.


Report C-2

Role of vitamin D and Parathyroid Hormone

in Microgravity-Induced Bone Loss

by Michael Holick


Introduction


Vitamin D and parathyroid hormone play important roles in bone metabolism. Therefore, any alteration in vitamin D and parathyroid hormone can potentially alter calcium metabolism, and have significant physiologic and pathologic consequences. Vitamin D must be metabolized in the liver to 25-hydroxy vitamin D (25-OH-D) which, in turn is metabolized in the kidney to 1,25-dihydroxyvitamin D (1,25(0H)2D3). It is now recognized that I,25(OH)2D3 is the biologically active form of vitamin D which is critically important for regulating the efficiency of intestinal calcium absorption. Monocytic precursor cells in the bone marrow possess receptors for (1,25(0H)2D3) (VDR) and are induced to mature, into osteoclasts by (1,25(0H)2D3). There is evidence to suggest that mature osteoclasts loose their VDR, and therefore, are no longer responsive to 1,25(0H)2D although recent evidence suggest that this may not necessarily be true. Mature osteoblasts also possess VDR and respond to 1,25(0H)2D by increasing the production of osteocalcin, osteopontin, and alkaline phosphatase. 1,25(0H)2D3 also regulates phosphorus metabolism by increasing intestinal phosphorus absorption especially in the lower small intestine.


Parathyroid hormone has a multitude of physiologic activities on both calcium and phosphorus metabolism. Parathyroid hormone enhances the tubular reabsorption of calcium in the proximal and distal convoluted tubules in the kidney. It also causes a phosphaturic effect. In the bone, monocytic precursor cells have receptors for PTH. PTH induces these cells to become mature osteoclasts. Once mature, the osteoclasts loose their receptor for PTH, and therefore, are no longer responsive to this hormone. Osteoblasts have receptors for PTH and there is strong evidence that PTH has an anabolic effect on bone especially on trabecular bone. PTH also can enhance intestinal calcium absorption indirectly and alter bone metabolism indirectly by its action on stimulating the renal production of 1,25(0H)2D.


Effect of Bed Rest Microgravity on the Vitamin D and PTH Axis.


A review of the literature from bed rest studies and from microgravity studies have suggested that once the bone is unloaded, there is an increase in the mobilization of calcium stores. This mobilization causes a slight rise in serum ionized calcium concentrations which, in turn, decreases the synthesis and secretion of PTH. The decrease in blood levels of PTH has a variety of physiologic effects. Most importantly, a decrease in the serum levels of PTH causes an increase loss of calcium into the urine. This can potentially increase the risk of developing kidney stones. The decrease in PTH may also decrease osteoblastic activity and therefore, bone formation. Since PTH also regulates phosphorus metabolism in the kidney; it is possible that the depressed production of PTH could lead to a small increase in fasting blood levels of serum phosphorus. PTH also indirectly regulates intestinal calcium absorption by regulating the renal production of 1,25(0H)2D. Therefore, when the blood levels of PTH are suppressed, there is a decrease in the metabolism of 25-0H-D to 1,25(0H)2D. This results in a decrease in intestinal calcium absorption


Therefore, a vicious cycle is established when the skeleton is unloaded, i.e., the body appears to depend on the bone for its major source of calcium since there is a significant decrease in intestinal calcium absorption presumably because of the decrease synthesis of 1,25(0H)2D. Therefore, when considering the calcium intake for astronauts, this issue needs to be carefully considered. Although it is reasonable for astronauts have an adequate amount of calcium in their diet, i.e., 800 to 1000 mg, it is probably not appropriate to substantially increase this level much beyond this. The reason for this that since the efficiency of intestinal calcium absorption is relatively low, the increase of calcium that remains in the intestine and ultimately evacuated in the stool could potentially alter gastrointestinal motility and cause constipation. It is unclear at this time whether the use of 1,25(0H)2D3 to enhance the efficiency of intestinal calcium absorption would be wise. The reason for this is that 1,25(0H)2D3, will definitely enhance intestinal calcium absorption. However, if bone formation is significantly decreased and cannot use this calcium, the increased absorption of calcium into the blood can ultimately increase calcium and the risk of kidney stones, hypercalcemia and soft tissue calcifications.


How Much Vitamin D is Required and what Should the Source of Vitamin D for Astronauts?


Most vitamin D for humans comes from exposure to sunlight. However, on the Shuttle and in the Space Station, the astronauts will not be exposed to any sunlight that could produce vitamin in their skin. Although the RDA for vitamin D in adults is 200 lU/day, there is evidence from our submarine study that suggests that in the absence of any exposure to sunlight, the RDA should be closer to 600 IU/day. Thus, a multivitamin that contains 400 to 600 of vitamin D should be adequate to maintain vitamin D stores in astronauts especially when on long duration flights.


An alternative method to provide, in a passive manner, vitamin D to astronauts is to incorporate into the lighting system a source of simulated sunlight that contains a small amount of ultraviolet B radiation. For example, a simulated sunlight source could be provided in a small area that is used as an active area. There is mounting evidence that exposure to ultraviolet radiation may have some beneficial effects for the body that not only includes the production of vitamin D, but also the feeling of well being due to the production of b-endorphins.


Conclusion


There is no question that microgravity-induce bone loss continues to be a significant physiologic adaptation that can have detrimental short-term and potentially long-term effects on astronauts. Therefore, there continues to be a need to better understand the mechanisms involved in microgravity-induced loss ant to develop counter measures to prevent it. From a hormonal point of view, there is strong evidence to suggest that the mobilization of calcium from the skeleton alters the PTH vitamin D axis. This ultimately results in a decrease in intestinal calcium absorption and the continual removal of calcium from the bone to satisfy the body's calcium requirement for its metabolic functions. It is important that the astronauts have an adequate dietary source of calcium probably in the range of 800 to 1000 mg/day along with an adequate source of vitamin D that approaches 600 IU/day. Consideration should be given to the incorporation of a simulated sunlight source for long-duration space flight as a mechanism to passively provide astronauts with their vitamin D requirement. The solar simulated light source may also provide them with other benefits as well including a feeling of well being.


There are a variety of other hormones that certainly can impact on both calcium and bone metabolism. Most notably, glucocorticoids can significantly alter calcium and bone metabolism. There is strong evidence to suggest that serum cortisol levels are increased in astronauts especially during the early part of their flight. Whether this is due to the stress of the flight or other causes is unclear at this time. There may be other hormonal factors such as IGF and its binding proteins that could be altered in microgravity and this requires further investigation.

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