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Postgraduate Training Course in Reproductive Health/Chronic Disease

 Osteoporosis in the frail elderly: A special case?

 René Rizzoli, M.D. and Jean-Philippe Bonjour, M.D.
Division of Bone Diseases
WHO Collaborating Center for the Prevention of Osteoporosis
Department of Internal Medicine
University Hospital
1211 Geneva 14

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I. Introduction

Among the determinants of osteoporosis in elderly, nutritional deficiencies certainly play a significant role. Indeed, undernutrition is often observed in elderly, and it appears to be more severe in patients with hip fracture than in the general aging population. A variety of evidences also leads to the conclusion that protein intake far below Recommended Daily Allowance could be particularly detrimental for both the acquisition of bone mass and the conservation of bone integrity with aging. Protein undernutrition can favor the occurrence of hip fracture by increasing the propensity to fall as a result of muscle weakness and of impairment in movement coordination, by affecting protective mechanisms, such as reaction time, muscle strength, and thus reducing the energy required to fracture an osteoporotic proximal femur, and/or by decreasing bone mass. Furthermore, a reduction in the protective layer of soft tissue padding decreases the force required to fracture an osteoporotic hip.

II. Osteoporotic fracture

Various studies have found a relationship between the level of protein intake and calcium-phosphate or bone metabolism and have come to the conclusion that either a deficient or an excessive protein supply could negatively affect the balance of calcium. An indirect argument in favor of a deleterious effect of high protein intake on bone is that hip fracture appears to be more frequent in countries with high protein intake of animal origin. But, as expected, the countries with the highest incidence of hip fracture are those with the longest life expectancy. In the large Nurse Health Study a trend for a hip fracture incidence inversely related to protein intake has been reported. Similarly, hip fracture was higher with low energy intake, low serum albumin levels and low muscle strength in the NHANES I study. In a prospective study carried out on more than 40'000 women in Iowa, higher protein intake was associated with a reduced risk of hip fracture. The association was particularly evident with protein of animal rather than vegetal origin. Similarly, a reduced relative risk of hip fracture was found with higher intake of milk. In another survey, no association between hip fracture and non-dairy animal protein intake could be detected. However, fracture risk was increased when a high protein diet was accompanied by a low calcium intake. Increasing protein intake has a favorable effect on BMD in elderly receiving calcium and vitamin D supplements. A low plasma albumin level has been repeatedly found in patients with hip fracture as compared to age-matched healthy subjects or to patients with osteoarthritis.

III. Bone mass

Regarding the relation with bone mineral mass, there was a positive correlation with spontaneous protein intake in premenopausal women, and bone mineral mass was directly proportional to serum albumin, taken as a reflection of nutritional intakes, in hip fracture patients. In a survey carried out in hospitalized elderly patients, low protein intake was associated with reduced femoral neck areal bone mineral density (BMD) and poor physical performances. The group with high protein intakes and a greater BMD, particularly at the femoral neck level, had also a better improvement of bicipital and quadricipital muscle strength and performance, as indicated by the increased capacity to walk and climb stairs, after four weeks of hospitalization. There was a positive correlation between radial bone mineral content and protein intake in Japanese or American women. In a longitudinal follow-up in the frame of the Framingham study, the rate of bone mineral loss was inversely correlated to dietary protein intake. In contrast, in a cross-sectional study, a protein intake close to 2 g/kg body weight was associated with reduced bone mineral density only at one out of two forearm sites in young college women. In the Study on Osteoporotic Fractures (SOF), an inverse relationship between bone mineral density changes and  the animal-to-vegetal protein ratio was found. The higher this ratio, the greater the bone loss. However, it would appear more relevant to compare with absolute protein intakes than with a ratio. Taken altogether, these results indicate that a sufficient protein intake is mandatory for bone health. Thus, whereas a gradual decline in calorie intake with age can been considered as an adequate adjustment to the progressive reduction in energy expenditure, the parallel reduction in protein intake may be detrimental for maintaining the integrity and function of several organs or systems, including skeletal muscles and bone.

IV. Relation with IGF-I

In association with the progressive age-dependent decrease in both protein intake and bone mass, several reports have documented a decrement in IGF-I plasma levels. Experimental and clinical studies suggest that dietary proteins, by influencing both the production and action of growth factors, particularly the Growth Hormone (GH)-Insulin-like Growth Factor (IGF) system, could influence bone homeostasis. The hepatic production and plasma level of IGF-I is under the influence of dietary proteins. Protein restriction has been shown to reduce IGF-I plasma levels by inducing a resistance to the action of GH at the hepatic level. Decreased serum IGF-I has been found in states of undernutrition such as marasmus, anorexia nervosa, celiac disease or HIV infected patients. Refeeding the patients led to an increase of IGF-I. Furthermore, elevated protein intake is able to prevent the decrease in IGF-I usually observed in hypocaloric states. In addition, protein restriction could render target organs less sensitive to IGF-I. When IGF-I was given to rats maintained under a low protein diet at doses normalizing its plasma levels, it failed to restore skeletal longitudinal growth. In addition, Growth hormone treatment was even associated with a decreased bone strength under conditions of a low protein diet.

V. Protein replenishment and osteoporosis

A state of undernutrition on admission, which is consistently documented in elderly patients with hip fracture, followed by an inadequate food intake during hospital stay can adversely influence their clinical outcome. Intervention studies using supplementary feeding by nasogastric tube or parenteral nutrition, or even a simple oral dietary preparation that normalizes protein intake can improve the clinical outcome after hip fracture. This way of correcting the deficient food intake has obvious practical and psychological advantages over nasogastric tube feeding or parenteral nutrition. It should be emphasized that in our studies a 20 g protein supplement brought the intake from low to a level still below RDA (0.8 g/kg body weight), avoiding thus the risk of an excess of dietary protein. Follow-up showed a significant difference in the clinical course in the rehabilitation hospitals, with the supplemented patients doing better. Although the mean duration of dietary supplementation did not exceed 30 days, the significantly lower rate of complication (bedsore, severe anemia, intercurrent lung or renal infections, 44% vs 87%) and of deaths (40% vs 74%) was still observed at six months. The duration of hospital stay of elderly patients with hip fracture is not only determined by the present medical condition, but also by domestic and social factors. In this study, the total length of stay in the orthopedic ward and rehabilitation hospitals was significantly shorter in supplemented patients than in controls (median: 24 vs 40 days). It was then shown that normalization of protein intake, independently of that of energy, calcium and vitamin D, was in fact responsible for this more favorable outcome. Finally, this normalization of protein intake was found to increase IGF-I, and even IgM concentrations. Thus, the lower incidence of medical complications observed after such a protein supplement is also compatible with the hypothesis of IGF-I improving the immune status, as this growth factor can stimulate the proliferation of immunocompetent cells and modulate immunoglobulins secretion.

Beside the production and action of the growth hormone-IGF-I system, protein undernutrition can be associated with alterations of cytokines secretion, such as interferon gamma, tumor necrosis factor alpha (TNF-alpha), or transforming growth factor beta. TNF-alpha and Interleukin-6 are generally increasing with aging. In a situation of cachexia, such as in chronic heart failure, an inverse correlation between bone mineral density and TNF-alpha levels has been found, further implicating a possible role of uncontrolled cytokines production in bone loss. Increased TNF-alpha can be a crucial factor in the sex hormone deficiency-induced bone loss, but it also plays a role in the target organ resistance to insulin, and possibly to IGF-I. Along the same line, certain amino acids given to rats fed a low protein diet can increase the liver protein synthesis response to TNF-alpha. The amino acid oxidation rate was lower in children with kwashiorkor, who were repleted with milk rather than with egg white, and protein breakdown and synthesis correlated inversely with TNF-alpha levels. The modulation by nutritional intakes of cytokines production and action, and the strong implication of various cytokines in the regulation of bone remodeling suggest a possible role of certain cytokines in the nutrition-bone link.

There is a large body of evidences linking nutritional intakes, particularly protein undernutrition and replenishment, to bone homeostasis and osteoporotic fractures. Several mechanisms, among them the growth hormone-IGF-I-target organ axis and various cytokines, are likely to be implicated.

VI. Protein replenishment and other systems

Besides bone, other systems can be damaged by protein undernutrition, and benefit from protein replenishment. Among them the immune or central nervous systems. Dietary protein, carbohydrate and fat enhance memory performance in elderly. A nutrition-dependent factor such as IGF-I has been recently found to decrease the deposition of beta-amyloid.


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