578 B. K. FORSCHER AND D. V. COHN 



The third would involve the binding of phosphate ions by conver- 

 sion of inorganic phosphate to organic phosphoric esters. Only the 

 first two of these mechanisms will be considered here, as it is thought 

 that the third is unlikely because of the high phosphatase activity 

 of bone. 



Unless specifically stated otherwise, all the data mentioned in this 

 review came from similar experiments. In general, parathyroid ex- 

 tract was administered to animals at one or more times, the animals 

 were sacrificed, and samples of bone were taken for in vitro metabolic 

 studies. Control values for comparison were obtained from similar 

 studies of samples of bone from normal, untreated animals. 



Let us consider first the possibility of a chelation mechanism. The 

 binding of calcium by citrate is a well known phenomenon and is 

 the basis for a theory to explain the demineralization of bone. The 

 theor\' holds that an excessive production of citrate occurs locally. 

 Although the major end product of the aerobic metabolism of glu- 

 cose by slices of bone is lactate, there is some Krebs cycle activity 

 ( Cohn and Forscher, 1962^ ) . The direct demonstration, in bone, of 

 some of the Krebs cvcle enzymes also has been reported (Balogh 

 et al., 1961; Kuhlman, 1960; Van Keen, 1959). An increased net 

 production of citrate bv lione in tissue culture was reported ( Kenny 

 et al., 1959) when incubations were carried out in an atmosphere 

 of 5 per cent CO2 in oxygen, as compared with incubations in 5 per 

 cent CO12 in air; even in this study, however, production of lactate 

 was 50 to 100 times greater than production of citrate. Thus, there 

 is no question that bone cells can produce citrate, but there is some 

 question as to whether significant concentrations of citrate accumu- 

 late and also whether parathyroid hormone influences this accumula- 

 tion. 



Production and oxidation of citrate liy bone from normal mice 

 and from mice treated with parathyroid hormone was studied by 

 Vaes and Nichols ( 1961 ) . They found the rate of citrate oxidation 

 in 5 per cent CO2 in air to be about 10 times greater than the rate 

 of citrate production. Although treatment with parathyroid hormone 

 increased the rate of production of citrate ( when further metabolism 

 was blocked), the rate of oxidation remained sufiiciently rapid to 

 more than handle the increased amounts of citrate. 



