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Bone and mineral metabolism in African Americans
Bone and Mineral Metabolism in Afkan Americans Norman
H. Bel1
Important differences exist in the metabolism of bone and mineral and the vitamin D endocline system between whites and African Ameticans and include rate ofskeletal remodeling, bone mass, and vitamin D metabolism. A higher bone mineral density (BMD) in Aftican Americans is associated with a diminished incidence of osteoporosis and fractures. Serum 17pestradiol and the rate of GH secretion are higher in black than in white men, hut there is NO racial difièrence in women in this regard. í%e mechanisms for reduced rate of skeletal remodeling and for greater BMD in blacks are not known, but diminished rate of skeletal remodeling could be a contributing factor for greuter bone mass. Reduction in serum 25 hydroxyvitamin D in blacks is attributed to increased skin pigment and to diminished dermal production of vitamin D, and consequent decreased hepatic synthesis of the metabolite. l%ere is no evidente that alteration of the vitamin D endocrine system contributes to or is responsible for racial differences in skeletal remodeling and bone mass. Black infants, howevev, are at risk for developing vitamin D-deficient rickets, particularly when (Trends Endocrinol Metab 1997;8:240-245). 0 1997, Elsevier breust-fed. Science Inc.
??
Osteoporosis and Fractures
The incidence of osteoporosis and fractures is lower in African Americans than in whites. Rates of hip fracture are more than 50% lower in African American than in white women (Kellie and Brody 1990, Griffin et al. 1992). A major factor responsible for the lower fracture rate in African Americans is a greater bone mass. The incidence of low bone mineral density (BMD) values as determined by prevalente of Z scores, that is, the number of standard deviations (SD) of a value in relation to mean value in young adult women, is much lower in African American than in white women at age 50 years but increases with aging so that by age 80 years a substantial number of
H. Bel1 is at the Department of Veterans Affairs Medical Center and Medical L’niversity of South Carolina, Charleston, SC 29401-5703, USA. Norman
240
them have values 2.5 SD below those of young adult women (Aloia et al. 1996). In women, a shorter hip axis length in Aftican American compared with white women may be a contributing factor (Cummings et al. 1994). A history of stroke, use of aids in walking, and consumption of alcohol are risk factors for fractures in African American women (Grisso et al. 1994), and reduced body weight is an important risk factor for low bone density and hip fracture in both African American and white women (Pruzansky et al. 1989).
??
Skeletal Remodeling
The rate of skeletal remodeling is lower in African American than in white men and women. Histomorphometric analysis of biopsies of the iliac crest after double-tetracycline labeling showed that bone formation rate in African American subjects was ody one third the value in white
0 1997, Ekvier
Science lx.,
1043-2760/97/$17.00
young adult men and women (Weinstein and Bel1 1988). In fact, al1 of the dynamic bone measurements were markedly different. In addition to bone formalion rate, mineralization perimeter and mineral apposition rate were lower, and mincralization lag time and formation period were longer in African Arnericans than in whites. On the other hand, static measurements were not significantly different in the two groups, including cortical width, cortical porosity, cancellous bone volume, trabecular width and spacing, osteoid area/total area, osteoblast perimeter, and osteoclast perimeter (Weinstein and Bel1 1988). When increased osteoid is not present, as found in this study, prolongation of mineralization lag time indicates a decrease in rate of synthesis of bone matrix and not abnormal mineralization or osteomalacia (Parfitt et al. 1985). A number of laboratories have shown that serum osteocalcin, an index of bone formation rate, is lower in African American than in white men and women (Bel1 et al. 1985, Meier et al. 1992, Kleerekoper et al. 1994, Odvina et al. 1995, Aloia et al. 1996). Serum bone-specific alkaline phosphatase also was lower in African American postmenopausal wromen (Kleerekoper et al. 1994). Some studies demonstrated that urinary hydroxyproline, a marker of bone resorption, is lower in African American than in both premenopausal and postmenopausal white women (Meier et al. 1992, Kleerekoper et al. 1994), whereas another study showed that urinary hydroxyproline was not racially different in premenopausal women and was significantly higher in white than in African American postmenopausal women (Aloia et al. 1996). Urinary N-telopeptide of type 1 collagen, a highly specific marker of bone resorption, is some 40% lower in African American than in white young adult men (Jackson et al. 1994). In boys and girls age 6 through 16 years, nocturnal urinary hydroxyproline is not racially different (Pratt et al. 1996); however, nocturnal urinary deoxypyridinoline and pyridinoline, markers of bone resorpti.on, are 10% to 15% lower in African American than in white children, but the differente is significant only in boys (Pratt et al. 1996). Thus, whereas results of studies with serum osteocalcin and histomorphometrit analysis of bone indicate a clear racial differente in bone formation, those
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TEM Vol. 8, No. 6, 1997
Table 1. The effects of race on bone mass in children BMD, Femoruf neck
BMD, f umbur Group Boys Aft-ican American White African Amcrican White Girls African American Whitc
N
Mefhod
14 16 20 33
DEXA
18 35
DPA
DPA
A C%)
1.6
0.61+0.01
7-12
0.8lrrO.02
7-12
Radiologie measurement of the metacarpal cortical area shows that African Americans have a greater skeletal mass than whites from 1 to 80 uears of agc (Owcn and Lubin 1973, Garn 1975). Total body BMD, determined bv dual-encrm x-ray absot-ptiometru (DEXA), is slightlu higher in African American than white infants 1 to 18 months of age (Rupich et al. 1996). Bone mineral content of the fbrearm, determined by single-photon absorptiometq, is greater in African American than in white children 1 to 6 uears of age (Li et al. 1989). As shown in Table 1, BMD of the lumbar spine and femoral neck, determined by DEXA, is 1.6% and 10.9% higher, respectivelu, in African American than in white prepubertal boys (White et al. 1997). BMD of’ the lumbar spine and femoral ncck, determined bu dual-photon absorptiornetry (DPA), is 3.8% and 12.5% higher, respectivelv, in African American than in white adolescent boys and is 13.8% and 17.6?k higher in Afkan
0
(Q/C& 0.7 1 ZO.02”
3.8
0.9020.03”
Sciencr
0 93?0.0_5~’ 0:8 110.01
Inc.,
104%2760/97/%1
Relerence
10.9
White et al. (1997)
12.5
Bel1 et al. (1991)
17.6
Bel1 et al. ( IYYl)
0.80~0.02 14.8
0.87?0.04” 0.74?0.01
American than in white adolescent girls (Bel1 et al. 1991). As shown in Table 2, BMD of the iumbar spine is 6.8% to 7.8% higher, and BMD of the femoral neck is 6.3% to 6.8% higher in African American than in white prcmenopausal women (Liel et al. 1988, Luckey et al. 1989, Meier et al. 1991 and 1992, Fleet et al. 1995). The values for BMD are comparable, whether determined bu DPA or DEXA. BMD of the lumbar spine is 9.6Lx, to 11.9% higher, and BMD of’ the femoral neck is 8.2% to 18.1% higher in Ai‘rican American than in white postmenopausal women (DeSimone et al. 1989, Meier et al. 1992, Kleerekoper et ai. 1994). Thc incidence of obesitu in older African American women is twice that in older white women. Because body weight is a major determinant of BMD, obesitu is a contributing factor to the greater bone mass in black women (DeSimone et al. 1989, Kleerekoper et al. 1994). Recent studies in which BMD was determined bu DEXA showed that the rate of bone loss at the lumbar spine and femoral neck is grcater in African American than in white women (Aloia et al. 1955). As shown in Table 3, BMD ofthe lumbar spine is 6.50/%to IO.IVC higher, and BMD of the femoral neck is 14.7% to 19.8% highcr in African American than in white men (Bel1 et al. 199.5, Nelson et al. 1995, Wr-ight et al. 1995). The differences are consistent whether determined hi- DPA or DEXA. Interestingly, bone loss produced bx chronic alcohol-
1997, Elsevirr
A (%)
0.64~0.02
0.78-tO.02
Bone Mass
TE.bf 1’01. 8. :x0. 6, 1997
6-7
spine @/cm?
0.60?0.02
oF studies with markers of bone resorption provide evidente for a racial difference of bone resorption in men and boys, a less consistent racial difierence in women, and no racial differente in girls as regards bone resorption. Whu the findings between differences in histomnrphometric findings and markers of skeletal remodrling in whites and African Americans are not morc consistent is not known.
??
4?e range CY>
i.00
ism is less in African American than in white men (Odvina et al. 1995). The cause for racial differenccs in bone mass is not known. Serum 17@ estradiol is a major determinant of GH in men and women, and in secretion men, it is derix;ed solely by aromatization fi-om testosterone, a biochemical went that is modulated by the enqme which is found predomiaromatase, na& in fat. Serum Up-estradiol and GH secretion are higher in African American than in white men (Wtight ct al. 19Y5), and 17P-estradiol is higher in African American than in white boys in late pubcrty (Richards ct al. 1992). GH secretion is not different in prepubertal African American compared with prepubertal white boys (Wright et al. 1997). Serum testosteronc was not racially different in the men and boys in these studies (Richards ct al. 1992, Wright el al. 1995 and 1997). Because body fat is lower in African American than in white men, the highet serum 17B-estradiol in African American men is attributed !o incrcascd aromatase. Bccause GH can increase bonc mass, thc greater production of t7@-estradiol and GH could contributc to the greater bone mass in African Amcrican men (Wright et al. 1995). On the othcr hand, serum testosterone but not GH secretion is higher in African American than in white women (Wright et al. 1996). A more recent studu found that serum testosterone is significantly higher in African American than in white postmenopausal women and that values are not different in premenopausal women (Aloia et al. 1996). Peuk
PI1 S1043-2760~97)0006.5-9
241
72 83 60 60 70 67
African American White
African American White
African American White
105 114
112 250
Afrícan American White
“~1C. 0.001 versus white. "p ~0.01 versuswhite ‘i> ~0.02 versuswhite. "p ~0.0001 versuswhite. BMD, hone mineral density: DEXA. dual-c~rrgy
Rcsults are mean 2 SE.
61 155
African American White
Perimenopausal and postmenopausal African American 62 White 81
African American White
and postmenopausal
72 110
Premenopausal women Ah-ican American White
Premenopausal
N
Group
x-rrty ahsorptiomctq;
DEXA
DPA
women DPA
DPA
women
DPA
DPA
DEXA
DPA
Method
6521 65% 1
6821 67% 1
53% 1 552 1
43 44
302 1 3021 3521 352 1 3721 3651
3521 3521
Age (YJ
DPA, single-photon
Table 2. The effects of race on bone mass in women
ahsorptiometry;
11.7
11.9
9.6
7.8
6.8
6.8
7.5
6.8
A (%J
ND, nat done.
1.05r0.02” 0.94?0.01
1.13*0.02” 1.01~0.01
1.14r0.02” 1.04cO.02
1.21 -‘O.Ol” 1.12+0.01
1.29-cO.02” 1.20+0.02 1.25+0.02” 1.17?0.02 1.25IrO.01” 1.17+0.01
1.26t0.02” 1.18-cO.01
BMD, lombar spine (g/cd)
0.82?0.01” 0.69r0.01
0.7920.03” 0.73’0.01
ND ND
ND ND
1.09-co.02” 1.02?0.02 ND ND ND ND
0.98t0.02” 0.92t0.01
neck (g/cd)
BMD, Femorai
18.1
8.2
6.8
6.5
A (‘W
Kleerekoper
DeSimone
et al. (1994)
et al. (1989)
Meier et al. (1992)
Luckeu et al. (1991)
Meier et al. (1991)
Meier et al. (1992)
Fleet et al. (1995)
Liel et al. (1988)
Reference
Table 3. The effects of race on bone mass in men
erm,
BMD, Lumbcrr Group African American White African American White African American White
N
Mefhod
40 DPA 59 16 DEXA 17 34 DEXA 160
bone mass is attained by the late teens to earl) twenties (Thejntz et al. 1992, Teegarden et al. 1995). The greater bone mass in African Amet-icans could occur because of increased intestinal absorption of calcium, diminished excretion of’ calcium, or both dwing adolescencc. One study
childhood
and
in adolescents indicates that urinary calcium is lower in African Amcrican than in white children and that intestinal absorption is not racially different (Bel1 et al. 1993). Another study dcmonstrates that intestina1 absorption of calcium is higher in African American than in white adolescent girls (Abrams et al. 1995). As noted, the rate oC skeletal remodeling is lower in Afì-ican American than in white men and women (Weinstein and Bel1 1988). Because bone mass declines with age and becausc age-related bone loss varies with the rate of skeletal remodeling, differenccs in the rate of skelctal remodeling could contribute to thc greatcr bonc mass in African American men and Lvomen.
??
Vitamin D Metabolism
The most important source ol‘vitamin D in humans is from dermal synthesis. Provitamin D, is produced f’rom 7-dehydrocholesterol by absorption of’one photon of sunlight, and pro\itamin D, is converted to vitamin D,, a tcmperaturc-dependent step, by body heat (Holick 198 1j. Vitamin D, has a high affinit‘; for vitamin D-binding globulin. It is taken up by dermal capillaries and is transported to the liver; whcre it undergoes 25-hydroxylation by action of thc enzymc vitamin D-25hydroxylase (Ponchon and DeLuca 1969). 25Hydroxycholecalciferol (25OHD) is fut-ther hydroxylated to 1.25dihydroxy-
7’EM w>1.x. No. h, 1997
R)IYY7,
spine
Me (Y)
cg/cm?
A (%l
31t1 3021 27%2 2722 5053 352 1
1.3210.03” 1.22kO.02 1.15CO.03 1.0810.03 1.20?0.03” 1.09t10.01
8.2 6.5 10.1
cholecalciferol
Femoral neck &J/cm? 1.17t0.03” 1.02to.02 1.081rO.03” 0.93kO.03 1.03 20.03“ 0.86%0.01
[ 1,25(OHj,D] in the kidney by action of the enzyne 25hydt-oxyvitamin D-lwhydroxylase, an event that is modulated positively by patathyoid hormone (Horiuchi et al. 1977) and insulinlike growth factor 1 (Caverzasio et al. 1990) and negatively by calcium (Bushinsky et al. 1985) and phosphorus (Portale et al. 1986). 1,25(OH),D and 25-OHD together promote intestinal absorption ot calcium (Favus 1985, Barger-Lux et al. J995). In African Americans, formation of provitamin D, and vitamin D, is impaired because photons are absorbed by melanin pigment in the dermis jnstead of by 7-dehydrocholesterol (Clemens et al. 1982). Thus. when black Africans move away from the equator and are cxposed to less intensc sunlight, vitamin D depletion occurs as a consequencc of diminished dermal production of uitamin D,. For exarnple, serum 25OHD in blacks was 29 rt 4 pg/mL (+ SE) in Zaire and 9 ? 1 pg/mL in Belgium (M’Buyamba-Kabangu et al. 1987). In African Americans of al1 ages (infants, adults, and children), a large number of studies indicate that serum 25-OHD is lower b>, about 50% (Bel1 ct al. 1985 and 1993, Hollis and Pittard 1984, Luckcy et al. 1989, Meier et al. 1991, Katz et al. 1992, Brickman et al. 1993, Dawson-Hughes et al. 1993, Fuleihan et al. 1994, Kleerekoper ct al. 1994, Abrams et al. 1995, Bel1 1995, Aloia et al. 1996). The lower serum 25OHD leads to mild sccondary hyper: parathyroidism, incrcascs in serum l,ZS(OH),D and urinary cAMP, and decreases in urinary calcium (Bel1 et al. 1985, Brickman et al. 1993, Fuleihan et al. 1994, Bel1 1995, Aloia et al. 199h). Treatment with 25OHD, reverses these changes: Serum 25OHD and winal?
Elsrviw Sciencc Inc., 1043-2760/97:F;17.00
A (%)
Reference
14.7
Bel1 et al. ( 1995)
16.1
Wright et al. (199.5)
19.8
Nclson ct al. (1995)
and serum 1,25 calcium increase, (OH),D and urinaru cAMP decrease (Bel1 1995). Studies of dynamic secretion of parathyroid hormone demonstrate exaggeration of enhanced secretion in response to hypocalcemia and decreased suppression of secretion in response to hypercalcemia in African Americans compared with whites (Fuleihan ct al. 1994). African Americans have Iarger parathyroid glands than whitcs at postmortcm examination (Ghandur-Mnaymneh et al. 1986). Vitamin D and 25OHD are stored in milk and provide a sourcc for nursing infants; however, the concentrations of vitamin D and 25OHD in milk arc so low that they providc only a ver? modcst proportion of nulritional necds (Chang et al. 1992). Because 01‘ lo\c maternal stores of 25-OHD both systemically and in rnilk, Af’rjcan American infants are at increased risk for developing vitamin D-deficient rickets with brcast-f’ecding (Chang et al. 1992, Key 1992). Four hundred IU of \?tamin D per day is the amount required for both term and premature infants to maintain a normal serum 2S-OHD (Hollis ct al. 1981). At present. thcrc is no cvidence that thc altcred state of lilamin D metabolism either contributes to or is responsibie for thc grcater bone mass in African Americans. Jt is evident that reduction in serum 25-OHD leads to reduction in urinar? calcium and a low incidence of nephrolithiasis in adults und to increascd incidence 01‘rickcts in inl’ants. Osteomalacia as a consequcncc of vitamin D deficicncy is nat described in African Americans.
PLl SlO43-2760(97)00065-9
243
??
Conclusions
In summaty, bone mass is higher and is a major factor in the lower incidence of osteoporosis and fractures in AFrican Americans than in whites. A lower rate of skeletal remodeling is probably a major factor in the racial differente in bone density. Future studies should be addressed at determining the mechanism for the racial differente in bone turnover. Alteration of the vitamin D endocrine system in African Americans is associated with increased risk of neonatal vitamin D-deficiency rickets and diminished inddence of calcium-containing kidney stones.
References Abrams SA, O’Brien KO, Liang LK, Stuff JE: 1995. Differences in calcium absorption and kinetics between black and white girls aged 5-16 years. J Bone Miner Res 10:829-833. Aloia JF, Vaswani A, Hey JK, Flaster E: 1996. Risk for osteoporosis in black women. Calcif lïssue Int 59:415-423. Batger-Lux MJ, Heaney RP, Lanspa SI, Healy JC, DeLuca HF: 1995. An investigation of sources of variation in calcium absorption efficiency. J Clin Endocrinol Metab 80~406-411. Bel1 NH: 1995. 25-Hydrox.vitamin D, reverses alteration of the vitamin D-endocrine system in bla&. Am J Med 99:597-599. Bel1 NH, Greene A. Epstein S, et al.: 1985. Evidence for aheration of the vitamin D-endocrine system in blacks. J Clin Invest 76:470473. BelJ NH, Shary J, Stevens J, et al.: 1991. Demonstration that bone mass is greater in black than in white children. J Bone Miner Res 6:719-723. Bell NH, Yergey AL, Vieira NE, Oexmann MJ, Shary JR: 1993. Demonstration of a difference in urinary calcium, not calcium absorption, in black and white adolescents. J Bone Miner Res 8:1111-1115. Bell NH, Cordon L, Stevens J. Shary J: 1995. Demonstmtion that bone mineral density of the lumbar spine, trochanter and femoral neck is higher in black than in white young men. Calcif Tissue Int 56:11-13. Brickman AS, Nydy MD, Griffiths RF, et al.: 1993. Racial diffetznces in platelet cytosolic calcium and calcitriopic hormones in normotensive subjects. Am J Hypertens 6:46-51. Bushinsky DA, Riera G, Mavus MJ, Coe FL: 1985. Evidente that blood ionized calcium can regulate serum 1,25(OH),D, independently of PTH and phosphorus in the rat. J Clin lnvest 76:1599-1604.
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Caverzasio J, Montessuit C, Bonjour JP: 1990. Stimulatory effect of insulin-like growth factor-1 on renal Pi transport and plasma 1,25dihydroxyvitamin D,. Endocrinology 127: 453-459. Chang YT Germain-Lee EL, Doran TF, et al.: 1992. Hypocalcemia in nonwhite breast-fed infants. Clin Pediat 3 1:695-698. Ciemens TL, Henderson SL, Adams JS, Holick MF: 1982. Increased skin pigment reduces the capacity of skin to synthesize titamin D,. Lancet 1:7476. Cummings SR, Cauley JA, Paleremo L, et al.: 1994. Racial differences in hip a>ris lengths might explain racial differences in rates of hip fracture. Osteopuros Int 4226-229. Dawson-Hughes B, Hart% S, Kramich C, et al.: 1993. Calcium retention and hormone levels in black and white women on high and low calcium diets. J Bone Miner Res 8:779-787. DeSimone DP, Stevens J, Edwa_rds J, et al.: 1989. Influence of body habitus and race on bone mineml density of the midradius, hip and spine in aging women. J Bone Miner Res 4827-830. Favus MJ: 1985. Factots that influence absorption and secretion of calcium in the smal1 intestine and colon. Am J Physiol 248:G147G157. Fleet JC, Harris SS, Wood RI, Dawson-Hughes B: 1995. The Bsml vitamin D receptor restriction fragment length polymorphism (BB) predicts Iow bone density in pre-menopausal black and white women. J Bone Miner Res 10:985-990. Fuleihan GE-H, Gundberg CM, Gleason R, et al.: 1994. Racial differences in parathyroid hormone dynamics. J Clin Endocrinol Metab 79: 1642-1647. Garn SM: 1975. Bone loss and aging. In Goldman R, Rockstein M, eds. Physiology and Pathology of Human Aging. New York, Academic Press, pp 39-57. Ghandur-Mnaymneh L, Cassady J, Hajanpour MA, Reiss E: 1986. The parathyroid gland in health and disease. Am J Pathol 125:292-299. Griflïn MR. Ray WA, Fought RL, Melton LH BI: 1992. Black-white differences in fmcture rates. Am J Epidemiol 136: 1378-1385. Grisso AJ, Kelsey JL. Strom BL, et al.: 1994. Risk factors for hip fracture in black women: the Northeast Hip Fracture Study Group. N Engl J Med 330: 1555-1559. Holick MF: 1981. The cutaneous synthesis of previtamin D,: a unique photoendocrine system. J Invest Dermatol 77:51-58. Hollis BW, Pittard WB 111:1984. Evaluation of the total fetomatemal vitamin D relationships at term: evidente for racial differences. J Clin Endocrinol Metab 59:652-657. Hollis BW, Roos BA, Draper HH, Lambert P\v 1981. Vitamin D and its metabolites in human and bovine milk. J Nutr 111: 1240-1248.
Horiuchi N, Suda T, Takahashi H. Shimazawa E, Ogata E: 1977. In vivo evidencc for the intermediary role of 3’,5’-cyclic AMP in parathyroid hormone-mediated stimulation of 1,25_dihydroxjvitamin D, synthesis in rats. Endocrinology 10 1:969-974. Jackson G, Hollis BW, Eyre DR. Baylink DJ, Bel1 NH: 1994. Effects of race and calcium intake on bone marken and calcium metabolism in young adult men [abst]. J Bone Miner Res 9:S185. Katz BS, Jackson GJ, Hollis BW, Bel1 NH: 1992. Diagnostic criteria of vitamin D deficiency. Endocrinologist 3:248-253. Kellie SE, Brody JA: 1990. Sex-specific and race-specific hip fracture rates. Am J Public Heahh 80~326-328. Key LL: 1992. Vitamin D deficiency Trends Endocrinol Metab 2~81-85.
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TEM Vol. 8,No.6,1997
Odvina CV, Suti 1, Wojtowica CH, et al.: 1995. EI’FectOf heavy alcohol intake in the abscncc 01 liver diseasc on bone mass in black and whitc men. J Clin Endocrinol Metab 80: 249Y-2503. Owvi GM, Lubin Alf: 1973. Anthropometric differenccs beth-een black and \\:hite preschool childrcn. Am J Dis Child 126: 168-169.
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differente
premenopausal
in bone women:
mineral
density
a clinical
in
research
center study J Clin Endocrinol 1023-1026.
Metab 81:
Wright NM, Wentz B, Papadea N, et al.: 1997. Growth hwmone secretion and bone mineral density in prepubertal black and whitc boys: a clinical crinol
research
Mrtab
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studx
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com-
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Pittard WR, Ceddes KM, Husley TC, Hollis BW 1991. How much Lritamin D for neonates? Am J Dis Child 145:1147--1149. Ponchon C, DeLuca HF: 1969. Thc role of the liver in the mctabolism of vitamin 0. J Clin Invrsl 48:1273-1279. Por& AA, Halloran BP, Mulphy MM, Mor-ris RC J~I 1986. Oml intake of phosphorus can determinc the wrum conccntration ol’ 1,23-dihy dnrqvitamin D b? dewrmining its production late in humans. J Clin [mest 77:7--12. Pratt Jll, Namalunga AK, Peacock M: 1996. A comparison of the urinan; rucretion of bone resorptiw products in Lvhitc and black childrcn. J Lab Clin Mcd 127:67-70. Pruzansky ME, Turano M, Luckey M, Senic R: 1989. Low body \veight is u risk factor for hip Irucn~rr in both black and white womcn. J Ot-ihop Rcs 7:192-197. Richards RJ, Svec F, Bai W, el al.: 1992. Stewid hormones cluring pubcrty: racial (blackwhite) diflewnccs in androstenrdione and cstradiol-thc Bogalusu Hcart Stud!. J Clin Endocrinol 75:624-43 1. Rupich RC, Specker BL, Lieuw-a-FA M, Ho M: Cender and race differences in bonc mass dwing
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D. Prc~ulx WR, Martin
Tecgnrclen 1995.
Calcif Tissue
bonc mass in )ounp
Pcak
Vitamin D and Hematopoiesis Christopher
M. Bunce, Geofffrey Brown, and Martin Hewison
Analysis of‘the nonclassic actions of‘vitamin
D, has highlighted u tuide
range of target tissues
1,25-dihydroxyvitamin
[1,25(OH),DJ.
for the hormone
Systemic or locally produced 1,25(OH),D,
in modulating cel1 development mechanisms
processes such as hematopoiesis.
by which 1,2S(OH),D,
D,,
may play a role The
achieves this are discussed in this
review. In particulat; data from our laboratolìes sqggest that 1,25(OH),D, does not provide a deterministic
signal for monocyte
dif&entiation.
Rathei; the hormone ucts as a permissive agent for myeloid precursor cells to enter a genetically determined terminal maturation pathwuy. The effìcacy of‘ I,25(OH),D,
in leukemia therapy bas been improved by the
development of‘novel vitamin D analogues thut have potent untiprolifèrative activity und low hypercalcemic side efects. Another solution to the problem of‘side efects is to enhance specificully the antiproliftirative efects of 1,25(OH),D,. A novel mechanìsm wìthìn hematopoietic cel1.q that governs their responsiveness to the antìprolìferative/diferentìative actìons of‘1,25(OH),D.,
is outlined.
(Trends Endocrinol
Metab 1997;8:245-25
1).
0 1997, Elsevier Scìence Inc.
BR. et al.: women. J
Bonc Miner Rcs 10:71 1-715. G, Buchs B, Rizzoli R. el al.: 1992. Longitudinal nwnitoring 01 bone mass accu-
Thcintz
mulation
in hcalth!
adolesccnts:
e\Aence
lok
16 yeals of age at \he Icvcls ot lumbar spine and femoral ncck in fcmale subjects. J Clin Endocrinol Mctab 75:1060-1065. u markcd
rcduction
after
Trechsel C, Bonjo~o~J-P, Fleisch H: 1978. Reglllation of the mctabolism of 25hydroxyvitamin D in primaty cultures OF chick kidne‘ celIs. J Clin Inwst 64:20&217.
Study of the nonclassic actions of steroid hormones has prolided US with ncw insight into their function and clinical application. A frequently cited example is the vitamin D endocrine system, which is now known to have effects far beyond its established calciotropic rolc (Walters 1992). In recent years, vitamin
N
C.M. Bunce, G. Brown, and M. Hewison are at the L.R.E Diffeferentiation Program al Cdrdifl and Birmingham; C.M. Bunce and G. Brown
NM. Rcnauit J, Willi S, et al.: 1995. Greatcr sccwtion of growth hormone in black than in white men: possible factor in
are also at the Department ofImmunology, Univcrsity of Birmingham, and Martin Hewison is at the Department of Medicine, Birmingham, University of Birmingham, Birmingham Bl 5 2TH, United Kingdom.
Weinstein RS. Bel1 NH: 1988. Diminishcd of bonc liwnution
in normal
rates
black adults.
Eng1 J Med 339:1698-1701. M’right
prcaler
bone
niincral
tlensit‘_a
7’IZ\d I:i)/. 8, No. 6, 1997
clinical
re-
D has been implicated in the development of skin and bloed cells and in controlling thc fimctional aclivity of cells of the immune system. These fïndings have nat only ernphasized the physiologjcal importante of vitamin D hut have highlighted its potential as a therapeutic agent in the treatment of skin and bloed disordcrs. Possible clinical applications for vitamin D include treatment of psoriasis and immunosuppression. These have been discussed in previous publications (Bouillon et al. 19951) und are only briefly descr-ibed hcre. The aim of this review is to focus on thc role of vitamin D in hematopoiesis and its possible use in the treatment of‘ leukemias.
si 1995, Elsevicr Sciencc Inc., 1031-2760/97!Fl7.00 PI1 S1043-27hO(Y7)OOOh6-0
245
H. Bel1
Important differences exist in the metabolism of bone and mineral and the vitamin D endocline system between whites and African Ameticans and include rate ofskeletal remodeling, bone mass, and vitamin D metabolism. A higher bone mineral density (BMD) in Aftican Americans is associated with a diminished incidence of osteoporosis and fractures. Serum 17pestradiol and the rate of GH secretion are higher in black than in white men, hut there is NO racial difièrence in women in this regard. í%e mechanisms for reduced rate of skeletal remodeling and for greater BMD in blacks are not known, but diminished rate of skeletal remodeling could be a contributing factor for greuter bone mass. Reduction in serum 25 hydroxyvitamin D in blacks is attributed to increased skin pigment and to diminished dermal production of vitamin D, and consequent decreased hepatic synthesis of the metabolite. l%ere is no evidente that alteration of the vitamin D endocrine system contributes to or is responsible for racial differences in skeletal remodeling and bone mass. Black infants, howevev, are at risk for developing vitamin D-deficient rickets, particularly when (Trends Endocrinol Metab 1997;8:240-245). 0 1997, Elsevier breust-fed. Science Inc.
??
Osteoporosis and Fractures
The incidence of osteoporosis and fractures is lower in African Americans than in whites. Rates of hip fracture are more than 50% lower in African American than in white women (Kellie and Brody 1990, Griffin et al. 1992). A major factor responsible for the lower fracture rate in African Americans is a greater bone mass. The incidence of low bone mineral density (BMD) values as determined by prevalente of Z scores, that is, the number of standard deviations (SD) of a value in relation to mean value in young adult women, is much lower in African American than in white women at age 50 years but increases with aging so that by age 80 years a substantial number of
H. Bel1 is at the Department of Veterans Affairs Medical Center and Medical L’niversity of South Carolina, Charleston, SC 29401-5703, USA. Norman
240
them have values 2.5 SD below those of young adult women (Aloia et al. 1996). In women, a shorter hip axis length in Aftican American compared with white women may be a contributing factor (Cummings et al. 1994). A history of stroke, use of aids in walking, and consumption of alcohol are risk factors for fractures in African American women (Grisso et al. 1994), and reduced body weight is an important risk factor for low bone density and hip fracture in both African American and white women (Pruzansky et al. 1989).
??
Skeletal Remodeling
The rate of skeletal remodeling is lower in African American than in white men and women. Histomorphometric analysis of biopsies of the iliac crest after double-tetracycline labeling showed that bone formation rate in African American subjects was ody one third the value in white
0 1997, Ekvier
Science lx.,
1043-2760/97/$17.00
young adult men and women (Weinstein and Bel1 1988). In fact, al1 of the dynamic bone measurements were markedly different. In addition to bone formalion rate, mineralization perimeter and mineral apposition rate were lower, and mincralization lag time and formation period were longer in African Arnericans than in whites. On the other hand, static measurements were not significantly different in the two groups, including cortical width, cortical porosity, cancellous bone volume, trabecular width and spacing, osteoid area/total area, osteoblast perimeter, and osteoclast perimeter (Weinstein and Bel1 1988). When increased osteoid is not present, as found in this study, prolongation of mineralization lag time indicates a decrease in rate of synthesis of bone matrix and not abnormal mineralization or osteomalacia (Parfitt et al. 1985). A number of laboratories have shown that serum osteocalcin, an index of bone formation rate, is lower in African American than in white men and women (Bel1 et al. 1985, Meier et al. 1992, Kleerekoper et al. 1994, Odvina et al. 1995, Aloia et al. 1996). Serum bone-specific alkaline phosphatase also was lower in African American postmenopausal wromen (Kleerekoper et al. 1994). Some studies demonstrated that urinary hydroxyproline, a marker of bone resorption, is lower in African American than in both premenopausal and postmenopausal white women (Meier et al. 1992, Kleerekoper et al. 1994), whereas another study showed that urinary hydroxyproline was not racially different in premenopausal women and was significantly higher in white than in African American postmenopausal women (Aloia et al. 1996). Urinary N-telopeptide of type 1 collagen, a highly specific marker of bone resorption, is some 40% lower in African American than in white young adult men (Jackson et al. 1994). In boys and girls age 6 through 16 years, nocturnal urinary hydroxyproline is not racially different (Pratt et al. 1996); however, nocturnal urinary deoxypyridinoline and pyridinoline, markers of bone resorpti.on, are 10% to 15% lower in African American than in white children, but the differente is significant only in boys (Pratt et al. 1996). Thus, whereas results of studies with serum osteocalcin and histomorphometrit analysis of bone indicate a clear racial differente in bone formation, those
PH SlO43-2760(97)00065-9
TEM Vol. 8, No. 6, 1997
Table 1. The effects of race on bone mass in children BMD, Femoruf neck
BMD, f umbur Group Boys Aft-ican American White African Amcrican White Girls African American Whitc
N
Mefhod
14 16 20 33
DEXA
18 35
DPA
DPA
A C%)
1.6
0.61+0.01
7-12
0.8lrrO.02
7-12
Radiologie measurement of the metacarpal cortical area shows that African Americans have a greater skeletal mass than whites from 1 to 80 uears of agc (Owcn and Lubin 1973, Garn 1975). Total body BMD, determined bv dual-encrm x-ray absot-ptiometru (DEXA), is slightlu higher in African American than white infants 1 to 18 months of age (Rupich et al. 1996). Bone mineral content of the fbrearm, determined by single-photon absorptiometq, is greater in African American than in white children 1 to 6 uears of age (Li et al. 1989). As shown in Table 1, BMD of the lumbar spine and femoral neck, determined by DEXA, is 1.6% and 10.9% higher, respectivelu, in African American than in white prepubertal boys (White et al. 1997). BMD of’ the lumbar spine and femoral ncck, determined bu dual-photon absorptiornetry (DPA), is 3.8% and 12.5% higher, respectivelv, in African American than in white adolescent boys and is 13.8% and 17.6?k higher in Afkan
0
(Q/C& 0.7 1 ZO.02”
3.8
0.9020.03”
Sciencr
0 93?0.0_5~’ 0:8 110.01
Inc.,
104%2760/97/%1
Relerence
10.9
White et al. (1997)
12.5
Bel1 et al. (1991)
17.6
Bel1 et al. ( IYYl)
0.80~0.02 14.8
0.87?0.04” 0.74?0.01
American than in white adolescent girls (Bel1 et al. 1991). As shown in Table 2, BMD of the iumbar spine is 6.8% to 7.8% higher, and BMD of the femoral neck is 6.3% to 6.8% higher in African American than in white prcmenopausal women (Liel et al. 1988, Luckey et al. 1989, Meier et al. 1991 and 1992, Fleet et al. 1995). The values for BMD are comparable, whether determined bu DPA or DEXA. BMD of the lumbar spine is 9.6Lx, to 11.9% higher, and BMD of’ the femoral neck is 8.2% to 18.1% higher in Ai‘rican American than in white postmenopausal women (DeSimone et al. 1989, Meier et al. 1992, Kleerekoper et ai. 1994). Thc incidence of obesitu in older African American women is twice that in older white women. Because body weight is a major determinant of BMD, obesitu is a contributing factor to the greater bone mass in black women (DeSimone et al. 1989, Kleerekoper et al. 1994). Recent studies in which BMD was determined bu DEXA showed that the rate of bone loss at the lumbar spine and femoral neck is grcater in African American than in white women (Aloia et al. 1955). As shown in Table 3, BMD ofthe lumbar spine is 6.50/%to IO.IVC higher, and BMD of the femoral neck is 14.7% to 19.8% highcr in African American than in white men (Bel1 et al. 199.5, Nelson et al. 1995, Wr-ight et al. 1995). The differences are consistent whether determined hi- DPA or DEXA. Interestingly, bone loss produced bx chronic alcohol-
1997, Elsevirr
A (%)
0.64~0.02
0.78-tO.02
Bone Mass
TE.bf 1’01. 8. :x0. 6, 1997
6-7
spine @/cm?
0.60?0.02
oF studies with markers of bone resorption provide evidente for a racial difference of bone resorption in men and boys, a less consistent racial difierence in women, and no racial differente in girls as regards bone resorption. Whu the findings between differences in histomnrphometric findings and markers of skeletal remodrling in whites and African Americans are not morc consistent is not known.
??
4?e range CY>
i.00
ism is less in African American than in white men (Odvina et al. 1995). The cause for racial differenccs in bone mass is not known. Serum 17@ estradiol is a major determinant of GH in men and women, and in secretion men, it is derix;ed solely by aromatization fi-om testosterone, a biochemical went that is modulated by the enqme which is found predomiaromatase, na& in fat. Serum Up-estradiol and GH secretion are higher in African American than in white men (Wtight ct al. 19Y5), and 17P-estradiol is higher in African American than in white boys in late pubcrty (Richards ct al. 1992). GH secretion is not different in prepubertal African American compared with prepubertal white boys (Wright et al. 1997). Serum testosteronc was not racially different in the men and boys in these studies (Richards ct al. 1992, Wright el al. 1995 and 1997). Because body fat is lower in African American than in white men, the highet serum 17B-estradiol in African American men is attributed !o incrcascd aromatase. Bccause GH can increase bonc mass, thc greater production of t7@-estradiol and GH could contributc to the greater bone mass in African Amcrican men (Wright et al. 1995). On the othcr hand, serum testosterone but not GH secretion is higher in African American than in white women (Wright et al. 1996). A more recent studu found that serum testosterone is significantly higher in African American than in white postmenopausal women and that values are not different in premenopausal women (Aloia et al. 1996). Peuk
PI1 S1043-2760~97)0006.5-9
241
72 83 60 60 70 67
African American White
African American White
African American White
105 114
112 250
Afrícan American White
“~1C. 0.001 versus white. "p ~0.01 versuswhite ‘i> ~0.02 versuswhite. "p ~0.0001 versuswhite. BMD, hone mineral density: DEXA. dual-c~rrgy
Rcsults are mean 2 SE.
61 155
African American White
Perimenopausal and postmenopausal African American 62 White 81
African American White
and postmenopausal
72 110
Premenopausal women Ah-ican American White
Premenopausal
N
Group
x-rrty ahsorptiomctq;
DEXA
DPA
women DPA
DPA
women
DPA
DPA
DEXA
DPA
Method
6521 65% 1
6821 67% 1
53% 1 552 1
43 44
302 1 3021 3521 352 1 3721 3651
3521 3521
Age (YJ
DPA, single-photon
Table 2. The effects of race on bone mass in women
ahsorptiometry;
11.7
11.9
9.6
7.8
6.8
6.8
7.5
6.8
A (%J
ND, nat done.
1.05r0.02” 0.94?0.01
1.13*0.02” 1.01~0.01
1.14r0.02” 1.04cO.02
1.21 -‘O.Ol” 1.12+0.01
1.29-cO.02” 1.20+0.02 1.25+0.02” 1.17?0.02 1.25IrO.01” 1.17+0.01
1.26t0.02” 1.18-cO.01
BMD, lombar spine (g/cd)
0.82?0.01” 0.69r0.01
0.7920.03” 0.73’0.01
ND ND
ND ND
1.09-co.02” 1.02?0.02 ND ND ND ND
0.98t0.02” 0.92t0.01
neck (g/cd)
BMD, Femorai
18.1
8.2
6.8
6.5
A (‘W
Kleerekoper
DeSimone
et al. (1994)
et al. (1989)
Meier et al. (1992)
Luckeu et al. (1991)
Meier et al. (1991)
Meier et al. (1992)
Fleet et al. (1995)
Liel et al. (1988)
Reference
Table 3. The effects of race on bone mass in men
erm,
BMD, Lumbcrr Group African American White African American White African American White
N
Mefhod
40 DPA 59 16 DEXA 17 34 DEXA 160
bone mass is attained by the late teens to earl) twenties (Thejntz et al. 1992, Teegarden et al. 1995). The greater bone mass in African Amet-icans could occur because of increased intestinal absorption of calcium, diminished excretion of’ calcium, or both dwing adolescencc. One study
childhood
and
in adolescents indicates that urinary calcium is lower in African Amcrican than in white children and that intestinal absorption is not racially different (Bel1 et al. 1993). Another study dcmonstrates that intestina1 absorption of calcium is higher in African American than in white adolescent girls (Abrams et al. 1995). As noted, the rate oC skeletal remodeling is lower in Afì-ican American than in white men and women (Weinstein and Bel1 1988). Because bone mass declines with age and becausc age-related bone loss varies with the rate of skeletal remodeling, differenccs in the rate of skelctal remodeling could contribute to thc greatcr bonc mass in African American men and Lvomen.
??
Vitamin D Metabolism
The most important source ol‘vitamin D in humans is from dermal synthesis. Provitamin D, is produced f’rom 7-dehydrocholesterol by absorption of’one photon of sunlight, and pro\itamin D, is converted to vitamin D,, a tcmperaturc-dependent step, by body heat (Holick 198 1j. Vitamin D, has a high affinit‘; for vitamin D-binding globulin. It is taken up by dermal capillaries and is transported to the liver; whcre it undergoes 25-hydroxylation by action of thc enzymc vitamin D-25hydroxylase (Ponchon and DeLuca 1969). 25Hydroxycholecalciferol (25OHD) is fut-ther hydroxylated to 1.25dihydroxy-
7’EM w>1.x. No. h, 1997
R)IYY7,
spine
Me (Y)
cg/cm?
A (%l
31t1 3021 27%2 2722 5053 352 1
1.3210.03” 1.22kO.02 1.15CO.03 1.0810.03 1.20?0.03” 1.09t10.01
8.2 6.5 10.1
cholecalciferol
Femoral neck &J/cm? 1.17t0.03” 1.02to.02 1.081rO.03” 0.93kO.03 1.03 20.03“ 0.86%0.01
[ 1,25(OHj,D] in the kidney by action of the enzyne 25hydt-oxyvitamin D-lwhydroxylase, an event that is modulated positively by patathyoid hormone (Horiuchi et al. 1977) and insulinlike growth factor 1 (Caverzasio et al. 1990) and negatively by calcium (Bushinsky et al. 1985) and phosphorus (Portale et al. 1986). 1,25(OH),D and 25-OHD together promote intestinal absorption ot calcium (Favus 1985, Barger-Lux et al. J995). In African Americans, formation of provitamin D, and vitamin D, is impaired because photons are absorbed by melanin pigment in the dermis jnstead of by 7-dehydrocholesterol (Clemens et al. 1982). Thus. when black Africans move away from the equator and are cxposed to less intensc sunlight, vitamin D depletion occurs as a consequencc of diminished dermal production of uitamin D,. For exarnple, serum 25OHD in blacks was 29 rt 4 pg/mL (+ SE) in Zaire and 9 ? 1 pg/mL in Belgium (M’Buyamba-Kabangu et al. 1987). In African Americans of al1 ages (infants, adults, and children), a large number of studies indicate that serum 25-OHD is lower b>, about 50% (Bel1 ct al. 1985 and 1993, Hollis and Pittard 1984, Luckcy et al. 1989, Meier et al. 1991, Katz et al. 1992, Brickman et al. 1993, Dawson-Hughes et al. 1993, Fuleihan et al. 1994, Kleerekoper ct al. 1994, Abrams et al. 1995, Bel1 1995, Aloia et al. 1996). The lower serum 25OHD leads to mild sccondary hyper: parathyroidism, incrcascs in serum l,ZS(OH),D and urinary cAMP, and decreases in urinary calcium (Bel1 et al. 1985, Brickman et al. 1993, Fuleihan et al. 1994, Bel1 1995, Aloia et al. 199h). Treatment with 25OHD, reverses these changes: Serum 25OHD and winal?
Elsrviw Sciencc Inc., 1043-2760/97:F;17.00
A (%)
Reference
14.7
Bel1 et al. ( 1995)
16.1
Wright et al. (199.5)
19.8
Nclson ct al. (1995)
and serum 1,25 calcium increase, (OH),D and urinaru cAMP decrease (Bel1 1995). Studies of dynamic secretion of parathyroid hormone demonstrate exaggeration of enhanced secretion in response to hypocalcemia and decreased suppression of secretion in response to hypercalcemia in African Americans compared with whites (Fuleihan ct al. 1994). African Americans have Iarger parathyroid glands than whitcs at postmortcm examination (Ghandur-Mnaymneh et al. 1986). Vitamin D and 25OHD are stored in milk and provide a sourcc for nursing infants; however, the concentrations of vitamin D and 25OHD in milk arc so low that they providc only a ver? modcst proportion of nulritional necds (Chang et al. 1992). Because 01‘ lo\c maternal stores of 25-OHD both systemically and in rnilk, Af’rjcan American infants are at increased risk for developing vitamin D-deficient rickets with brcast-f’ecding (Chang et al. 1992, Key 1992). Four hundred IU of \?tamin D per day is the amount required for both term and premature infants to maintain a normal serum 2S-OHD (Hollis ct al. 1981). At present. thcrc is no cvidence that thc altcred state of lilamin D metabolism either contributes to or is responsibie for thc grcater bone mass in African Americans. Jt is evident that reduction in serum 25-OHD leads to reduction in urinar? calcium and a low incidence of nephrolithiasis in adults und to increascd incidence 01‘rickcts in inl’ants. Osteomalacia as a consequcncc of vitamin D deficicncy is nat described in African Americans.
PLl SlO43-2760(97)00065-9
243
??
Conclusions
In summaty, bone mass is higher and is a major factor in the lower incidence of osteoporosis and fractures in AFrican Americans than in whites. A lower rate of skeletal remodeling is probably a major factor in the racial differente in bone density. Future studies should be addressed at determining the mechanism for the racial differente in bone turnover. Alteration of the vitamin D endocrine system in African Americans is associated with increased risk of neonatal vitamin D-deficiency rickets and diminished inddence of calcium-containing kidney stones.
References Abrams SA, O’Brien KO, Liang LK, Stuff JE: 1995. Differences in calcium absorption and kinetics between black and white girls aged 5-16 years. J Bone Miner Res 10:829-833. Aloia JF, Vaswani A, Hey JK, Flaster E: 1996. Risk for osteoporosis in black women. Calcif lïssue Int 59:415-423. Batger-Lux MJ, Heaney RP, Lanspa SI, Healy JC, DeLuca HF: 1995. An investigation of sources of variation in calcium absorption efficiency. J Clin Endocrinol Metab 80~406-411. Bel1 NH: 1995. 25-Hydrox.vitamin D, reverses alteration of the vitamin D-endocrine system in bla&. Am J Med 99:597-599. Bel1 NH, Greene A. Epstein S, et al.: 1985. Evidence for aheration of the vitamin D-endocrine system in blacks. J Clin Invest 76:470473. BelJ NH, Shary J, Stevens J, et al.: 1991. Demonstration that bone mass is greater in black than in white children. J Bone Miner Res 6:719-723. Bell NH, Yergey AL, Vieira NE, Oexmann MJ, Shary JR: 1993. Demonstration of a difference in urinary calcium, not calcium absorption, in black and white adolescents. J Bone Miner Res 8:1111-1115. Bell NH, Cordon L, Stevens J. Shary J: 1995. Demonstmtion that bone mineral density of the lumbar spine, trochanter and femoral neck is higher in black than in white young men. Calcif Tissue Int 56:11-13. Brickman AS, Nydy MD, Griffiths RF, et al.: 1993. Racial diffetznces in platelet cytosolic calcium and calcitriopic hormones in normotensive subjects. Am J Hypertens 6:46-51. Bushinsky DA, Riera G, Mavus MJ, Coe FL: 1985. Evidente that blood ionized calcium can regulate serum 1,25(OH),D, independently of PTH and phosphorus in the rat. J Clin lnvest 76:1599-1604.
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Caverzasio J, Montessuit C, Bonjour JP: 1990. Stimulatory effect of insulin-like growth factor-1 on renal Pi transport and plasma 1,25dihydroxyvitamin D,. Endocrinology 127: 453-459. Chang YT Germain-Lee EL, Doran TF, et al.: 1992. Hypocalcemia in nonwhite breast-fed infants. Clin Pediat 3 1:695-698. Ciemens TL, Henderson SL, Adams JS, Holick MF: 1982. Increased skin pigment reduces the capacity of skin to synthesize titamin D,. Lancet 1:7476. Cummings SR, Cauley JA, Paleremo L, et al.: 1994. Racial differences in hip a>ris lengths might explain racial differences in rates of hip fracture. Osteopuros Int 4226-229. Dawson-Hughes B, Hart% S, Kramich C, et al.: 1993. Calcium retention and hormone levels in black and white women on high and low calcium diets. J Bone Miner Res 8:779-787. DeSimone DP, Stevens J, Edwa_rds J, et al.: 1989. Influence of body habitus and race on bone mineml density of the midradius, hip and spine in aging women. J Bone Miner Res 4827-830. Favus MJ: 1985. Factots that influence absorption and secretion of calcium in the smal1 intestine and colon. Am J Physiol 248:G147G157. Fleet JC, Harris SS, Wood RI, Dawson-Hughes B: 1995. The Bsml vitamin D receptor restriction fragment length polymorphism (BB) predicts Iow bone density in pre-menopausal black and white women. J Bone Miner Res 10:985-990. Fuleihan GE-H, Gundberg CM, Gleason R, et al.: 1994. Racial differences in parathyroid hormone dynamics. J Clin Endocrinol Metab 79: 1642-1647. Garn SM: 1975. Bone loss and aging. In Goldman R, Rockstein M, eds. Physiology and Pathology of Human Aging. New York, Academic Press, pp 39-57. Ghandur-Mnaymneh L, Cassady J, Hajanpour MA, Reiss E: 1986. The parathyroid gland in health and disease. Am J Pathol 125:292-299. Griflïn MR. Ray WA, Fought RL, Melton LH BI: 1992. Black-white differences in fmcture rates. Am J Epidemiol 136: 1378-1385. Grisso AJ, Kelsey JL. Strom BL, et al.: 1994. Risk factors for hip fracture in black women: the Northeast Hip Fracture Study Group. N Engl J Med 330: 1555-1559. Holick MF: 1981. The cutaneous synthesis of previtamin D,: a unique photoendocrine system. J Invest Dermatol 77:51-58. Hollis BW, Pittard WB 111:1984. Evaluation of the total fetomatemal vitamin D relationships at term: evidente for racial differences. J Clin Endocrinol Metab 59:652-657. Hollis BW, Roos BA, Draper HH, Lambert P\v 1981. Vitamin D and its metabolites in human and bovine milk. J Nutr 111: 1240-1248.
Horiuchi N, Suda T, Takahashi H. Shimazawa E, Ogata E: 1977. In vivo evidencc for the intermediary role of 3’,5’-cyclic AMP in parathyroid hormone-mediated stimulation of 1,25_dihydroxjvitamin D, synthesis in rats. Endocrinology 10 1:969-974. Jackson G, Hollis BW, Eyre DR. Baylink DJ, Bel1 NH: 1994. Effects of race and calcium intake on bone marken and calcium metabolism in young adult men [abst]. J Bone Miner Res 9:S185. Katz BS, Jackson GJ, Hollis BW, Bel1 NH: 1992. Diagnostic criteria of vitamin D deficiency. Endocrinologist 3:248-253. Kellie SE, Brody JA: 1990. Sex-specific and race-specific hip fracture rates. Am J Public Heahh 80~326-328. Key LL: 1992. Vitamin D deficiency Trends Endocrinol Metab 2~81-85.
rickets.
Kleerekoper M, Nelson DA, Peterson EL, et al.: 1994. Reference data for bone mass, calciotropie hormones, and biochemical markers of bone remodeling in older (55-75) postmenopausal white and black women. J Bone Miner Res 8:1267-1276. Li J-Y, Specker BL, Ho ML, Bone mineral content in children 1 to 6 years of age: of race and sex differences. 143:13461349.
Tsang RC: 1989. black and white early appearance Am J Dis Child
Liel Y, Edwards J, Shary J, et al.: 1988. The effects of race and body habitus on bone mineral density of the radius, hip and spine in premenopausal women. J Clin Endocrinol Metab 66:1247-1250. Luckey MM, Meier DE, Mandeli HP, et ai.: 1989. Axial and appendicular bone density in white and black women: evidente of mcial differences in premenopausal bone homeostasis. J Clin Endocrinol Metab 69:762-770. M’Buyamba-Kabangu JR, Fagard R, Lijnen P, et al.: 1987. Calcium, vitamin D-endocrine system and parathyroid hormone in black and white males. Calcif lïssue Int 41:70-74. Meier DE, Luckey MM, Wallenstein S. et al.: 199 1. Calcium, vitamin D and parathyroid hormone status in young white and black women: association with racial differences in bone mass. J Clin Endocrinol Metab 72:703710. Meier DE, Luckey MM, Wallenstein S, Lapinski RH, Cather-wood B: 1992. Racial differences in pre- and postmenopausal bone homeostasis: association with b«ne density J Bone Miner Res 7:1181-1189. Modlin M: 1967. Urinary calcium in normal adults and in patients with renal stones: an interracial study. Invest Urol 5:49-57. Nelson DA, Jacobsen G, Barondcss DA, Parfitt AM: 1995. Ethnic differences in regional bone density, hip axis length, and lifestyle variables among healthy black and white men. J Bone Miner Res !0:782-787.
0 1997, Elsevier Science Inc., 1043-2760/97/$17.00PI1 SI 043-2760(97)00065-9
TEM Vol. 8,No.6,1997
Odvina CV, Suti 1, Wojtowica CH, et al.: 1995. EI’FectOf heavy alcohol intake in the abscncc 01 liver diseasc on bone mass in black and whitc men. J Clin Endocrinol Metab 80: 249Y-2503. Owvi GM, Lubin Alf: 1973. Anthropometric differenccs beth-een black and \\:hite preschool childrcn. Am J Dis Child 126: 168-169.
search center study 80:22Yl-2297.
J Clin Endocrinol
Metab
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Calcif Tissue
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Vitamin D and Hematopoiesis Christopher
M. Bunce, Geofffrey Brown, and Martin Hewison
Analysis of‘the nonclassic actions of‘vitamin
D, has highlighted u tuide
range of target tissues
1,25-dihydroxyvitamin
[1,25(OH),DJ.
for the hormone
Systemic or locally produced 1,25(OH),D,
in modulating cel1 development mechanisms
processes such as hematopoiesis.
by which 1,2S(OH),D,
D,,
may play a role The
achieves this are discussed in this
review. In particulat; data from our laboratolìes sqggest that 1,25(OH),D, does not provide a deterministic
signal for monocyte
dif&entiation.
Rathei; the hormone ucts as a permissive agent for myeloid precursor cells to enter a genetically determined terminal maturation pathwuy. The effìcacy of‘ I,25(OH),D,
in leukemia therapy bas been improved by the
development of‘novel vitamin D analogues thut have potent untiprolifèrative activity und low hypercalcemic side efects. Another solution to the problem of‘side efects is to enhance specificully the antiproliftirative efects of 1,25(OH),D,. A novel mechanìsm wìthìn hematopoietic cel1.q that governs their responsiveness to the antìprolìferative/diferentìative actìons of‘1,25(OH),D.,
is outlined.
(Trends Endocrinol
Metab 1997;8:245-25
1).
0 1997, Elsevier Scìence Inc.
BR. et al.: women. J
Bonc Miner Rcs 10:71 1-715. G, Buchs B, Rizzoli R. el al.: 1992. Longitudinal nwnitoring 01 bone mass accu-
Thcintz
mulation
in hcalth!
adolesccnts:
e\Aence
lok
16 yeals of age at \he Icvcls ot lumbar spine and femoral ncck in fcmale subjects. J Clin Endocrinol Mctab 75:1060-1065. u markcd
rcduction
after
Trechsel C, Bonjo~o~J-P, Fleisch H: 1978. Reglllation of the mctabolism of 25hydroxyvitamin D in primaty cultures OF chick kidne‘ celIs. J Clin Inwst 64:20&217.
Study of the nonclassic actions of steroid hormones has prolided US with ncw insight into their function and clinical application. A frequently cited example is the vitamin D endocrine system, which is now known to have effects far beyond its established calciotropic rolc (Walters 1992). In recent years, vitamin
N
C.M. Bunce, G. Brown, and M. Hewison are at the L.R.E Diffeferentiation Program al Cdrdifl and Birmingham; C.M. Bunce and G. Brown
NM. Rcnauit J, Willi S, et al.: 1995. Greatcr sccwtion of growth hormone in black than in white men: possible factor in
are also at the Department ofImmunology, Univcrsity of Birmingham, and Martin Hewison is at the Department of Medicine, Birmingham, University of Birmingham, Birmingham Bl 5 2TH, United Kingdom.
Weinstein RS. Bel1 NH: 1988. Diminishcd of bonc liwnution
in normal
rates
black adults.
Eng1 J Med 339:1698-1701. M’right
prcaler
bone
niincral
tlensit‘_a
7’IZ\d I:i)/. 8, No. 6, 1997
clinical
re-
D has been implicated in the development of skin and bloed cells and in controlling thc fimctional aclivity of cells of the immune system. These fïndings have nat only ernphasized the physiologjcal importante of vitamin D hut have highlighted its potential as a therapeutic agent in the treatment of skin and bloed disordcrs. Possible clinical applications for vitamin D include treatment of psoriasis and immunosuppression. These have been discussed in previous publications (Bouillon et al. 19951) und are only briefly descr-ibed hcre. The aim of this review is to focus on thc role of vitamin D in hematopoiesis and its possible use in the treatment of‘ leukemias.
si 1995, Elsevicr Sciencc Inc., 1031-2760/97!Fl7.00 PI1 S1043-27hO(Y7)OOOh6-0
245