2005

J Gerontol A Biol Sci Med Sci. 2001 Mar;56(3):B98-107.
Calorie restriction and skeletal mass in rhesus monkeys (Macaca mulatta): evidence for an effect mediated through changes in body size.
Black A, Allison DB, Shapses SA, Tilmont EM, Handy AM, Ingram DK, Roth GS, Lane MA.
Molecular and Nutritional Physiology Unit, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.

Little is known regarding the effects of prolonged calorie restriction (CR) on skeletal health. We investigated long-term (11 years) and short-term (12 months) effects of moderate CR on bone mass and biochemical indices of bone metabolism in male rhesus monkeys across a range of ages. A lower bone mass in long-term CR monkeys was accounted for by adjusting for age and body weight differences. A further analysis indicated that lean mass, but not fat mass, was a strong predictor of bone mass in both CR and control monkeys. No effect of short-term CR on bone mass was observed in older monkeys (mean age, 19 years), although young monkeys (4 years) subjected to short-term CR exhibited slower gains in total body bone density and content than age-matched controls. Neither biochemical markers of bone turnover nor hormonal regulators of bone metabolism were affected by long-term CR. Although osteocalcin concentrations were significantly lower in young restricted males after 1 month on 30% CR in the short-term study, they were no longer different from control values by 6 months on 30% CR.

2001

J Nutr 2001 Mar;131(3):820-7.
Energy restriction does not alter bone mineral metabolism or reproductive cycling and hormones in female rhesus monkeys.
Lane MA, Black A, Handy AM, Shapses SA, Tilmont EM, Kiefer TL, Ingram DK, Roth GS.
Laboratory of Neurosciences, National Institute on Aging, Gerontology Research Center, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.

Energy restriction (ER) extends the life span and slows aging and age-related diseases in short-lived mammalian species. Although a wide variety of physiological systems have been studied using this paradigm, little is known regarding the effects of ER on skeletal health and reproductive aging. Studies in rhesus monkeys have reported that ER delays sexual and skeletal maturation in young male monkeys and reduces bone mass in adult males. No studies have examined the chronic effects on bone health and reproductive aging in female rhesus monkeys. The present cross-sectional study examined the effects of chronic (6 y) ER on skeletal and reproductive indices in 40 premenopausal and perimenopausal (7-27 y old) female rhesus macaques (Macaca mulatta). Although ER monkeys weighed less and had lower fat mass, ER did not alter bone mineral density, bone mineral content, osteocalcin, 25-hydroxyvitamin D, 1,25-hydroxyvitamin D or parathyroid hormone concentrations, menstrual cycling or reproductive hormone concentrations. Body weight and lean mass were significantly related to bone mineral density and bone mineral content at all skeletal sites (total body, lumbar spine, mid and distal radius; P: < or = 0.04). The number of total menstrual cycles over 2 y, as well as the percentage of normal-length cycles (24-31 d), was lower in older than in younger monkeys (P: < or = 0.05). Older monkeys also had lower estradiol (P: = 0.02) and higher follicle-stimulating hormone (P: = 0.02) concentrations than did younger monkeys. We conclude that ER does not negatively affect these indices of skeletal or reproductive health and does not alter age-associated changes in the same variables.

1995

Clin Endocrinol Metab 1995 Dec;80(12):3628-33.
Decreased bone formation and increased mineral dissolution during acute fasting in young women.
Grinspoon SK; Baum HB; Kim V; Coggins C; Klibanski A.
AUTHOR AFFILIATION: Neuroendocrine Unit, Massachusetts General Hospital, Boston 02114, USA.

ABSTRACT: Severe chronic undernutrition is associated with decreased bone turnover and significant bone loss. However, little is known about the short-term effects of nutritional deprivation on bone turnover. To investigate the effects of short-term fasting on bone metabolism and the contribution of acidosis to these changes, 14 healthy women ages 18-26 (mean, 21 +/- 2 (SD years) were randomized to potassium bicarbonate (KHCO3, 2 meq/kg/day in divided doses) to prevent acidosis or control (potassium chloride, 25 meq/day) during a complete 4-day fast. Bone turnover was assessed using specific markers of formation [osteocalcin (OC) and Type I procollagen carboxyl-terminal propeptide (PICP)] and resorption [pyridinoline (PYRX) and deoxypyridinoline (DPYRX)]. Serum bicarbonate levels fell significantly from 27.0 +/- 3.2 to 17.3 +/- 2.6 mmol/L (P < 0.01) in the control group and were decreased compared to patients receiving KHCO3 [17.3 +/- 2.6 vs. 23.4 +/- 2.4 mmol/L, (P < 0.001)]. Serum total and ionized calcium increased significantly in the control group [9.1 +/- 0.1 to 9.4 +/- 0.2 mg/dL (P < 0.01) and 1.20 +/- 0.03 to 1.23 +/- 0.03 mmol/L (P < 0.05), respectively], but not in patients receiving KHCO3. In addition, serum parathyroid hormone (PTH) levels decreased from 32 +/- 17 to 16 +/- 10 pg/mL (P < 0.05) and urinary calcium excretion increased [86 +/- 51 to 182 +/- 103 mg/day (P = 0.01)] in the control group, but not in patients receiving KHCO3. Serum osteocalcin (OC) and procollagen carboxyl-terminal propeptide (PICP) levels decreased significantly after 4 days of fasting from 9.1 +/- 3.4 to 5.5 +/- 4.2 ng/mL (P < 0.01) and 121 +/- 21 to 46 +/- 13 ng/mL (P = 0.0001) respectively in the patients receiving bicarbonate, and from 10.1 +/- 3.3 to 4.0 +/- 2.9 ng/mL (P < 0.01) and from 133 +/- 22 to 47 +/- 19 ng/mL (P < 0.001) respectively in the control group. The decrease in osteocalcin and PICP during fasting was comparable in both treatment groups. By contrast, urinary excretion of PYRX and DPYRX did not change significantly in either group with 4 days of fasting. These data are the first to demonstrate that markers of bone formation decline significantly with short-term fasting, independent of changes in acid-base status. By contrast, these data demonstrate a direct effect of acidosis in stimulating calcium release from bone during short-term fasting and suggest that acidosis may increase mineral dissolution independent of osteoclast activation and PTH in this experimental model of acute starvation. AAC comments: This paper give us a sound message that we have to implement alkaline, carbonate water intake during fasting days.

J Clin Invest 1995 Aug;96(2):900-6.
Effects of rhIGF-I administration on bone turnover during short-term fasting.
Grinspoon SK; Baum HB; Peterson S; Klibanski A.
Neuroendocrine Unit, Massachusetts General Hospital, Boston 02114, USA.

Insulin-like growth factor-I (IGF-I) is a nutritionally dependent bone trophic hormone which stimulates osteoblast function and collagen synthesis in vivo and in vitro. We hypothesized that in the fasting state, IGF-I levels would decline significantly and would establish a model in which we could investigate the effects of IGF-I administration on bone turnover. We therefore studied 14 normal women ages 19-33 (mean, 24 +/- 4 [SD] years) during a complete 10-d fast. After 4 d of fasting, subjects were randomized to receive rhIGF-I or placebo subcutaneously twice a day for 6 d. Bone turnover was assessed using specific markers of formation (osteocalcin and type I procollagen carboxyl-terminal propeptide [PICP]) and resorption (pyridinoline, deoxypyridinoline, type I collagen crosslinked N-telopeptide [N-telopeptide] and hydroxyproline). Serum levels of PICP and osteocalcin decreased from 143 +/- 52 to 60 +/- 28 ng/ml (P = 0.001) and from 7.6 +/- 5.4 to 4.2 +/- 3.1 ng/ml (P = 0.001) respectively with 4 d of fasting. Urinary excretion of pyridinoline and deoxypyridinoline decreased from 96 +/- 63 to 47 +/- 38 nmol/mmol creatinine (P < 0.05) and from 28 +/- 17 to 14 +/- 11 nmol/mmol creatinine (P < 0.05) respectively. Mean IGF-I levels decreased from 310 +/- 81 to 186 +/- 78 ng/ml (P = 0.001). In the second part of the experimental protocol, serum osteocalcin and PICP levels increased 5- and 3-fold, respectively with rhIGF-I administration and were significantly elevated compared with the placebo group at the end of treatment (20.9 +/- 17.3 vs. 5.9 +/- 6.4 ng/ml for osteocalcin [P < 0.05] and 188 +/- 45 vs. 110 +/- 37 ng/ml for PICP [P < 0.05]). In contrast, all four markers of bone resorption, including urinary pyridinoline, deoxypyridinoline, N-telopeptide and hydroxyproline were unchanged with rhIGF-I administration. This report is the first to demonstrate that bone turnover falls rapidly with acute caloric deprivation in normal women. RhIGF-I administration uncouples bone formation in this setting by significantly increasing bone formation, but not resorption. These data suggest a novel use of rhIGF-I to selectively stimulate bone formation in states of undernutrition and low bone turnover.