Resistance to Bone Resorbing Effects of PTHin Black Women

FELICIA COSMAN,1,2 DORCAS C. MORGAN,1 JERI W. NIEVES,1,2 VICTOR SHEN,1,2

MARJORIE M. LUCKEY,3 DAVID W. DEMPSTER,1,2 ROBERT LINDSAY,1,2 and MAY PARISIEN1,2

ABSTRACT

Black women have a lower incidence of vertebral and hip fractures than white women, possibly due to differencesin skeletal and mineral metabolism. One suggested mechanism is that blacks have decreased skeletal sensitivityto parathyroid hormone (PTH). To test this hypothesis, we infused h(1–34)PTH in healthy premenopausal black(n5 15) and white (n5 18) women over 24 h andmeasured serum and urine indices of bone turnover and calciummetabolism throughout the infusion. At baseline, the mean 25-hydroxyvitamin D (25(OH)D) concentration wassignificantly lower in black women (46%). There were also nearly significant trends toward higher PTH and lowerurinary calcium and pyridinoline levels in black women. During infusion, there were no racial differences in themean (1–34)PTH levels achieved or in resultant elevations of serum calcium or 1,25-dihydroxyvitamin D(1,25(OH)2D) levels. Endogenous parathyroid suppression (measured by (1–84)PTH levels) was also similarbetween blacks and whites. There was an initial decline in urinary calcium/creatinine in both groups with a greaterreduction in black women early in the infusion period ( p < 0.05 at 8 h). Furthermore, blacks had lower levels ofurinary calcium/creatinine throughout the infusion ( p < 0.05 group difference). Bone formation markers (car-boxy-terminal propeptide of type I procollagen and osteocalcin) decreased within 8 h and continued to declinethroughout the infusion with no distinguishable racial differences ( p < 0.05 time trend for both). The mostdramatic difference between black and white women in response to PTH infusion was represented by the boneresorption markers. Three separate metabolites of bone resorption (cross-linked N-telopeptide of type I collagen,cross-linked C-telopeptide of type I collagen, and free pyridinoline) all showed substantially greater elevations inwhite (mean peak increments 399, 725, and 43%) compared with black women (mean peak increments 317, 369,and 17%) during the infusion ( p< 0.05 group differences for all three variables). These data strongly suggest thatblacks have decreased skeletal sensitivity to the acute resorptive effects of increased PTH. This finding indicatesthat calcium homeostasis may be accomplished in blacks (during times of relative calcium deficiency) by greaterconservation of calcium from nonskeletal sources (most likely renal) with relative preservation of skeletal tissue.These differences in calcium economy could account, at least in part, for the increased bone mass and lowerincidence of osteoporotic fractures in black women. (J Bone Miner Res 1997;12:958–966)

INTRODUCTION

RACIAL DIFFERENCES in the incidence of osteoporotic frac-tures are well established, with blacks having a lower

incidence of vertebral compression fractures(1) and hipfractures(2–7) than whites. This difference has been attrib-

uted at least in part to a higher bone mineral density inblacks.(8–15) Investigations into the etiology of the racialdisparity in bone mass have revealed differences in calciummetabolism and bone turnover, with the most consistentfinding being lower urinary calcium excretion in blackscompared with whites.(13–19) In addition, numerous studies

1Regional Bone/Clinical Research Centers, Helen Hayes Hospital, West Haverstraw, New York, U.S.A.2Columbia University, New York, New York, U.S.A.3Mount Sinai Hospital, New York, New York, U.S.A.

JOURNAL OF BONE AND MINERAL RESEARCHVolume 12, Number 6, 1997Blackwell Science, Inc.q 1997 American Society for Bone and Mineral Research

958

have documented lower 25-hydroxyvitamin D (25(OH)D)levels in black women(15,17–23) with higher parathyroid hor-mone (PTH) levels also reported in several studies.(15,17,20)

Lower levels of osteocalcin,(14,15,17) bone-specific alkalinephosphatase,(15) and urinary hydroxyproline(14,15) suggestthat black women might have lower bone turnover despitehigher PTH levels. Consequently, it was theorized, initiallyby Bell et al.,(17) that blacks have decreased skeletal sensi-tivity to PTH. In the present investigation, this hypothesis wastested directly by infusing h(1–34)PTH and evaluating theskeletal response, using biochemical remodeling indices, incomparable groups of healthy black and white premenopausalwomen.

MATERIALS AND METHODS

Subjects

Healthy premenopausal black (n 5 15) and white (n 518) women between the ages of 25 and 40 years wererecruited from New York City, and Rockland and OrangeCounties (NY, U.S.A.), through poster, newspaper, radio,and television advertisements. Participants were required tohave a normal menstrual history and be in good health asassessed by medical history, physical examination, electro-cardiogram, blood count, and serum chemistries, includingliver and thyroid function tests. Women were required to bewithin 80–120% of ideal body weight for height and framesize as determined by the 1983 Metropolitan Life Insurancetables.(24) Potential subjects with medical conditions ordrug exposure known to affect bone metabolism were ex-cluded. Specifically, women with a recent history (within 6months prior to participation) or current use of oral con-traceptive or corticosteroid medications were excluded. Nosubjects were on thyroid hormone or calcium supplements.All patients gave written informed consent, and the studywas approved by the Institutional Review Board of HelenHayes Hospital.

Infusion protocol

Infusions were performed during the follicular phase ofthe menstrual cycle (within 2 weeks of the last menstrualperiod). Between 3:00 and 4:00 p.m., two baseline bloodsamples and one urine sample were obtained. Beginning at4:00 p.m., synthetic h(1–34)PTH (Rhone-Poulenc Rorer,Horsham, PA, U.S.A.) dissolved in normal saline was in-fused continuously by indwelling intravenous catheter at arate of 0.55U/kg/h for a period of 24 h as previously de-scribed.(25,26) The women maintained light activity and in-gested no more than 600 mg of calcium and 1000 mg ofphosphorus throughout the investigation, as ordered by anutritionist. Blood and urine samples were collected at 4-hintervals for a total of 24 h, after which the intravenouscatheters were removed and the patients discharged home.

Circadian rhythm assessment protocol

To assure that changes in bone turnover markers weredue to PTH infusion rather than the underlying diurnal

rhythm of bone remodeling, a subgroup of black (n 5 5)and white (n5 4) women who underwent the PTH infusionwere also admitted for serial blood and urine sampling (4hourly) over a 24-h period using an otherwise identicalprotocol but without infusion. These investigations werealso performed during the follicular phase of the menstrualcycle and at least 8 weeks after the initial PTH infusionprocedure.

Biochemical determinations

Serum (1–34)PTH was analyzed using chicken antibodyCK67 in a radioimmunoassay(27) and (1–84)PTH by immu-noradiometric assay (Allegro Intact PTH, Nichols Institute,San Juan Capistrano, CA, U.S.A.). Serum 25(OH)D and1,25-dihydroxyvitamin D (1,25(OH)2D) were analyzed bycompetitive protein binding and radioreceptor assays.(28,29)

Serum ionized calcium was analyzed by standard techniques(NOVA 8 ionized calcium analyzer, Newton, MA, U.S.A.).Quality control information for these assays have beenpublished previously.(25,26)

Serum samples were also obtained for analysis of boneformation markers, including osteocalcin (BGP) by immu-noradiometric assay (human osteocalcin, Nichols Institute,CA) and carboxyterminal propeptide of type I procollagen(PICP) by radioimmunoassay (INCSTAR Corp., Stillwater,MN, U.S.A.). The minimum detectable concentrationswere 0.01 nmol/l for BGP and 1.2 ng/ml for PICP. Interas-say and intra-assay coefficients of variation were 10.6 and6.1% for BGP, and 8.6 and 4.9% for PICP.Urine calcium and creatinine were analyzed by standard

techniques. Calcium and creatinine clearance were calcu-lated using standard formulas.Three urine bone resorption markers were all measured

by ELISA assays, with results corrected for urine creatinine:free pyridinoline (PYD/Cr, Pyrilinks, Metra Biosystems,Mountain View, CA, U.S.A.)(30); cross-linked N-telopep-tide of type 1 collagen (NTX/Cr, Osteomark, Ostex Int.,Seattle, WA)(31); and cross-linked C-telopeptide of Type Icollagen (CTX/Cr, Crosslaps, Osteometer, Glerupvej, Den-mark).(32) The interassay and intraassay coefficients of vari-ation were 13.4 and 2.6%; 9.2 and 6.1%; 9.2 and 6.2%,respectively.

Statistical analysis

All statistical analyses were performed using the SASstatistical program (SAS Institute, Cary, NC, U.S.A.). Themean and standard error are reported for each baselinevariable. Unpaired Student’s t-tests were used to comparebaseline values between black and white women for nor-mally distributed variables and nonparametric tests used forvariables that were not normally distributed. Repeatedmeasures analysis of variance was used to determine signif-icance of time trends, overall group differences, differencesin incremental or decremental changes between groups atspecific time points, and group differences in the temporalcourse of responses (time/group interactions). To deter-mine whether baseline biochemical levels could account inpart for skeletal responsivity, Pearson correlation coeffi-

RACIAL DIFFERENCES IN PTH RESPONSIVITY 959

cients were determined between baseline variables andpeak increments in skeletal resorption indices.

RESULTS

Subjects

Descriptive characteristics of the subjects are shown inTable 1. There were no significant differences between thetwo groups in age, height, educational level, or parity. Meanbody weight and body mass index of the black women wereslightly higher than those of the white women ( p , 0.05 forthe latter variable). Routine chemistry, thyroid, gonadal,and hematology profiles were normal in all women andsimilar between the groups (data not shown). Characteris-tics of the subgroups of black and white women admittedfor assessment of diurnal rhythmic variation in bone turn-over markers did not differ significantly from their respec-tive total groups or from each other (data not shown).

Basal biochemistry

For each patient, two basal values were averaged(Table 1) to minimize fluctuation due to pulsatile hormonesecretion. The major difference between the groups was asignificantly lower mean basal 25(OH)D level in blackwomen (46% difference, p 5 0.006). In general, mean basal(1–84)PTH was lower in whites, and mean urinary calcium/creatinine lower in blacks, but these differences did notquite meet statistical significance ( p , 0.07). In general,mean indices of bone formation and resorption were similarbetween the two infusion groups and between the twocontrol subgroups (data not shown), although PYD wasslightly lower in black women (p , 0.07).

Effects of PTH infusion

Calcium homeostasis: During the infusion, serum concen-trations of PTH(1–34) rose promptly (Fig. 1), with peakconcentrations of 16.62 6 2.6 pmol/l in white women and18.676 2.1 pmol/l in black women, with no significant racialdifferences. Levels remained elevated throughout the infu-sion. Serum ionized calcium rose in both groups within 4 hand continued to rise throughout the investigation with nodifferences between black and white women. In both groups,endogenous PTH(1–84) declined significantly below baselinewithin 4 h, with continued suppression throughout the study.Serum 1,25(OH)2D levels increased significantly in bothgroups within 8 h and continued to rise through 20 and 24 h inblacks and whites, respectively. There were no racial differ-ences. Serum 25(OH)D levels remained unchanged through-out the infusion in both racial groups (data not shown).Significant time trends were seen in both groups for

urinary calcium/creatinine (UCa/Cr, p , 0.01). Levels de-creased below baseline in black and white women for atleast 16 h, but within 20 h UCa/Cr levels were elevated atwhich time mean serum calcium levels exceeded 1.39mmol/l in both groups. Throughout the investigation,UCa/Cr levels were lower in black than in white womenwith an overall group difference ( p , 0.05). Decrementsfrom baseline differed at the 8 h time with black womenshowing greater renal calcium conservation than whitewomen ( p , 0.05). Analysis of calcium clearance correctedfor creatinine clearance revealed the same results asUCa/Cr (data not shown).Bone formation markers: In control patients undergoing

the serum sampling protocol for assessment of diurnalrhythms in biomarkers (with no infusion), there were slightfluctuations (maximum of approximately 10%) in both se-

TABLE 1. CHARACTERISTICS OF STUDY POPULATIONSMEAN 6 SEM

Black (n 5 15) White (n 5 18) p value

Descriptive variablesage (years) 33.506 1.40 33.30 6 1.00 NSheight (m) 1.646 0.02 1.65 6 0.02 NSweight (kg) 65.236 1.94 61.06 6 1.31 0.08BMI (kg/m2) 24.31 6 0.77 22.40 6 0.58 0.05education (years) 15.406 0.65 15.44 6 0.65 NSparity 1.40 6 0.40 1.10 6 0.30 NScalcium intake (mg/day) 6336 109 650 6 86 NS

Calcium homeostasis variablesPTH(1–84) (pmol/l) 3.946 0.30 3.21 6 0.29 0.062Ca12 (mmol/l) 1.21 6 0.007 1.20 6 0.006 NS25(OH)D (nmol/l) 34.606 5.10 63.80 6 5.60 0.0061,25(OH)2D (pmol/l) 72.88 6 5.00 73.92 6 4.91 NSurinary Ca/Cr (mmol/mmol) 0.256 0.05 0.36 6 0.04 0.069

Bone turnover variablesosteocalcin (nmol/l) 0.956 0.07 1.00 6 0.04 NSPICP (ng/ml) 94.506 7.90 97.40 6 7.90 NSpyridinoline/Cr (nmol/mmol) 20.606 1.01 23.94 6 1.39 0.069N-telopeptide/Cr (nMBCE/mMCr) 22.716 2.87 23.18 6 2.84 NSC-telopeptide/Cr (ng/l/mMCr) 81.006 6.80 76.50 6 6.00 NS

960 COSMAN ET AL.

rum BGP and PICP levels (Fig. 2), over the 24 h period.There were no significant differences between groups foreither of these variables under control conditions.With PTH infusion, both serum BGP, and even more

markedly, serum PICP, decreased in both groups within 8 h

and declined to nadir levels at 20 h (time trends p , 0.05).Group responses were very similar.Bone resorption markers: All resorption markers showed

evidence of a natural diurnal rhythm, with peak levels at8 a.m. and nadir levels at 4 p.m. to midnight (Fig. 3). Black

FIG. 1. Changes in calcium homeostasis variables during 24-h (1–34)PTH infusion in black ■ and white F women.†represents time trend. *denotes overall group difference. **denotes difference in decrement at specific time point. (Allp , 0.05 by repeated measures ANOVA.) (Top panels, left to right) Serum (1–34)PTH (pmol/l), serum ionized calcium(mmol/l), serum (1–84)PTH (pmol/l). (Bottom panels) Serum 1,25(OH)2D (pmol/l) and urinary calcium/creatinine(mmol/mmol). For (1–34)PTH, ionized calcium, (1–84)PTH, and 1,25(OH)2D, significant time trends were seen, but therewere no group differences. For urinary calcium/creatinine, the group difference was significant and the decrement at 8 hwas greater in blacks than in whites.

FIG. 2. Changes in bone formation variables during 24 h of (1–34)PTH infusion in black■ and whiteF women are shownin continuous lines. Changes in control subjects who underwent same sampling protocol without PTH infusion are shownin dashed lines, ■ for black and F for white women. Symbols refer only to (1–34)PTH infused groups: †represents timetrend, p , 0.05 by repeated measures ANOVA. (Left panel) Serum BGP (nmol/L). (Right panel) PICP (ng/ml). Therewere significant time trends with infusion for both variables in blacks and whites but no racial differences. There was nosignificant time trend for the two control groups.

RACIAL DIFFERENCES IN PTH RESPONSIVITY 961

and white women did not differ significantly in this circa-dian pattern or the degree of variation in resorption markerlevels over 24 h.In response to PTH infusion, NTX/Cr and CTX/Cr in-

creased in both white and black women (time trend p ,0.005; Fig. 3). Responses of these peptide-bound pyridino-line markers were substantially higher, however, in whitecompared with black women ( p , 0.003 group differencefor both NTX/Cr and CTX/Cr). Mean peak NTX/Cr inwhite women was 1126 16 versus 746 8 nMBCE/mMCr inblack women, corresponding to 399 and 317% incrementsover baseline, respectively. Substantial differences in meanpeak levels of CTX/Cr were also seen (in white, 4486 24 vs.303 6 12 mg/l/mMCr in black, or 725 and 369% incrementsover baseline, respectively). Incremental changes at multi-ple specific times were also higher in white than blackwomen, and an overall racial difference in the temporalcourse of response (time/group interaction) was seen forCTX/Cr ( p , 0.02).Free PYD/Cr increased above diurnal rhythm variation

only in white women with a peak increment of 43% overbaseline. In black women, PYD/Cr did increase with time(mean peak 17%) but this increase did not differ fromdiurnal variation. Both an overall group difference ( p ,

0.003) and a racial difference in the temporal course ofresponse (time/group interaction, p , 0.07) were seen forthis variable.The relationship between free PYD/Cr and peptide-

bound pyridinolines (NTX/Cr and CTX/Cr) differed de-pending on the total level of bone resorption. Figure 4illustrates that, in both races, the ratio of free PYD/Cr tototal measured pyridinolines in urine (free 1 peptidebound) decreases substantially as total pyridinolines in-crease. There were no racial differences in the relationshipbetween free and peptide-bound pyridinolines.Interactions between basal vitamin D status and bone re-

sorption response: Linear correlations were determined be-tween baseline 25(OH)D and peak resorption marker in-crements as well as baseline PTH and peak resorptionincrements. In black women, there were no significant oreven close to significant relationships. In white women,there were weak positive correlations between 25(OH)Dand resorption marker increments and weak negative cor-relations between PTH and resorption marker increments.None of these was statistically significant. In black andwhite women combined, correlation coefficients between25(OH)D and resorption marker increments varied from0.30 for PYD/Cr to 0.38 for NTX/Cr (p , 0.03 for NTX/Cr,

FIG. 3. Changes in bone resorption variables during 24 h of (1–34)PTH infusion in black ■ and white F women areshown in continuous lines. Changes in control subjects who underwent same sampling protocol without PTH infusion areshown in dashed lines, ■ for black and F for white women. Symbols refer only to (1–34)PTH infused groups, as follows:†represents time trend; *denotes overall group difference; **denotes difference in increment at specific time point;‡denotes time/group interaction. (All p , 0.05 by repeated measures ANOVA, except time/group interaction forPYD/Cr 5 0.07.) (Top panel) Urine NTX/Cr (nMBCE/mMCr) and urine CTX/Cr (mg/L/mMCr). (Bottom panel)Urine-free PYD/Cr (nmol/mmol). For the control groups, time trends were seen for both black and white women (nosymbols on graph) without group differences or time/group interactions. There were significant time trends for both blackand white infusion groups for all variables, but the PYD response was not greater in the infused black group than in eithercontrol group. Group differences were seen for all variables. Time/group interactions were seen for CTX/Cr and freePYD/Cr.

962 COSMAN ET AL.

p , 0.09 for PYD/Cr and CTX/Cr). Relationships betweenbasal PTH levels and peak resorption marker incrementswere somewhat weaker. Only the correlation with the peakCTX/Cr increment and basal PTH was close to significant(r 5 20.33, p 5 0.08 vs. r 5 20.13 for PYD/Cr and 20.14for NTX/Cr).The influence of baseline 25(OH)D was also investigated

by analyzing the NTX/Cr and CTX/Cr responses to PTHinfusion with 25(OH)D as an independent variable. The racialgroup difference persisted for CTX/Cr ( p , 0.003) and justmissed significance for NTX/Cr ( p 5 0.10). There was asignificant time/race interaction term for both CTX/Cr ( p 50.007) and NTX/Cr ( p5 0.043) with 25(OH)D considered asa covariate.To elucidate further the possible influence of basal vita-

min D status on resorption response to PTH infusion,subgroups of subjects were identified whose 25(OH)D lev-els could be matched with those from the other racialgroup. Due to the large racial difference in 25(OH)D, onlyfive women within each race had comparable 25(OH)Dlevels, with resultant mean levels of 50.9 nmol/l in white and50.3 nmol/l in black women. The response of NTX/Cr toPTH was elevated in the white subgroup compared with theblack subgroup to the same extent as that seen for thewhole groups. Mean peak NTX/Cr was 122 6 24 nMBCE/mMCr in whites (407% elevation) and 72 6 16 nMBCE/Crin blacks (313% elevation; group difference, p , 0.058).Similarly, the CTX/Cr response was greater in these white(peak 429 6 49 mg/l/mMCr) versus black (peak 321 6 42)women (group difference, p 5 0.032). As in the largergroups, a slightly greater PYD/Cr increment was also seenin the subgroup of white women compared with the blacksubgroup.

DISCUSSION

Based on previous findings of higher PTH with lowerlevels of bone turnover markers (hydroxyproline and osteo-calcin) in black women, it was hypothesized that blackwomen might be resistant to the skeletal effects of parathy-roid hormone.(17) Similar racial differences observed inmore recent investigations(14,15,20) supported this hypothe-sis. We now present dynamic data providing the first direct

evidence that black women are less sensitive to the boneresorbing effects of acute increments in PTH, with substan-tially lower increments in biochemical markers of boneresorption in response to PTH infusion in black comparedwith white women. We also affirmed the finding of overallsuperior renal calcium conservation in black women(13–19)

and demonstrated a somewhat greater renal calcium con-servation response to PTH infusion, particularly in the earlypart of the protocol. Even small differences in renal calciumhandling have the potential to result in significant effects oncalcium homeostasis and help preserve the skeleton.Our baseline data confirmed previous findings of signif-

icantly lower 25(OH)D levels in blacks compared withwhites.(15,17–23) In our study, lack of significant differencesin mean basal PTH, urinary calcium, and bone turnovervariable levels between blacks and whites was probably dueto our small sample size. This study was designed to inves-tigate changes in response to dynamic perturbations andmay not have been large enough to detect baselinedifferences.Serum BGP and PICP, both markers of osteoblastic ac-

tivity, have well documented circadian rhythms with a noc-turnal rise and morning decline.(33–38) Control subjects ofboth races in this study exhibited little rhythmicity in eitherserum BGP or PICP. This might have been due to our smallsample size and an overall smaller absolute change in levelsexpected with bone formation variables, in contrast to re-sorption variables. More frequent serum sampling mighthave made the diurnal variation in BGP and PICP moreobvious. The circadian rhythm of the resorption mark-ers,(39–41) with peak levels in the early morning and thenadir in late afternoon or early evening, was seen in ourinvestigation and did not differ between blacks and whites.In both blacks and whites, PTH infusion resulted in a

small decline in BGP levels and a more marked decrementin serum PICP. Differences in responsivity of PICP versusBGP might be due to a variety of factors including expres-sion at different points during osteoblast development, dif-ferential sensitivity of gene expression of the two moleculesin response to PTH stimulation, or differential stability inthe circulation and/or clearance rates of the two com-pounds. Decreases in bone formation variables have beenseen with previous PTH challenge studies in humans,(42,43)

as well as in the rat(44) and in vitro studies.(45) This acute

FIG. 4. Relationship of free pyr-idinoline to total pyridinoline-con-taining collagen breakdown productsin black and white women. All valuesfrom individual patients at all timepoints prior to and during PTH infu-sion are included. Total pyridinolinevalue is estimated by the addition oflevels of N-telopeptide and free pyr-idinoline. Free fraction 5 free PYDdivided by the total.

RACIAL DIFFERENCES IN PTH RESPONSIVITY 963

suppression of bone formation contrasts with the effects ofchronic endogenous elevations of PTH such as in primaryhyperparathyroidism,(46) and with results of exogenousPTH administration by subcutaneous injection, where bothbone formation and resorption variables are increased.(47)

Major racial differences in response to PTH infusionwere seen with bone resorption indices where significantlyhigher elevations of all three variables (NTX/Cr, CTX/Cr,PYD/Cr) occurred in white compared with black women,despite the same increment in PTH levels. In black women,the lack of response of free PYD/Cr to infusion differedfrom the responses of the peptide-bound pyridinoline re-sorption markers, where increments above diurnal rhythmpeaks were seen. Similarly, increments seen in white womenwere of much lower magnitude with PYD/Cr than witheither NTX/Cr or CTX/Cr. Although all of these markershave validity as measures of bone resorption based oneither histomorphometric or kinetic studies,(33,46) clearlythey do not reflect exactly the same process, or are metab-olized differently. Perhaps during acute substantial incre-ments in bone resorption, less pyridinoline is excreted in itsfree form due to less complete collagen digestion at theosteoclast level or less time for peripheral metabolism.Proportionately more, at that time, would be liberated inthe peptide-bound form. Consistent with this hypothesis isthe finding that the fraction of free pyridinoline to totalpyridinoline becomes smaller as total pyridinoline, and thustotal resorption, becomes greater. This could explain whythe free pyridinoline response in white women (43% peakelevation above baseline) was less robust than the peakN-telopeptide or C-telopeptide responses (399–725% forwhite women). If this is true, the significantly lower freepyridinoline response expected (in contrast to peptide-bound pyridinoline) in black women might have been dif-ficult to see with this assay.A traditional interpretation of the phenomenon of skel-

etal resistance to PTH in black women is that it developedas an adaptive response to help protect the skeleton fromrelative vitamin D deficiency. Indeed, in our larger study ofnormal premenopausal black and white women, 72% ofblacks but only 11.5% of whites had 25(OH)D levels #37.5nmol/l (unpublished data), consistent with data fromNHANES, a large population-based study.(23) Our investi-gation suggests that these differences in basal vitamin Dbetween black and white women contributed only weakly, ifat all, to the difference in resorption response to PTH. Weconsidered the possibility that, in black women, increasedambient levels of PTH in basal conditions (induced by lowvitamin D) might result in down-regulation of PTH recep-tors. This down-regulation, in turn, could decrease skeletalresponsivity to exogenously administered PTH. The lack ofrelationships between basal 25(OH)D and PTH with re-sorption marker increments in black women did not supportthis thesis. There was a suggestion that basal vitamin Dstatus in white women might be associated with resorptionresponse to exogenous PTH, suggesting perhaps a moreimportant physiological role for 25(OH)D in white women.Even when the data from the black and white women werecombined, the weak relationships detected between basal25(OH)D and skeletal responsivity would explain only 10–

15% of the variance in skeletal responsivity at best. Thiscombined analysis, however, cannot eliminate the effect ofrace itself and does not therefore directly address the issueof the 25(OH)D level as a predictor of skeletal response toPTH. Furthermore, in the full racial groups, when25(OH)D levels were considered as independent variablesin the analysis of variance of the resorption marker re-sponse to PTH infusion, the racial differences persisted.Similarly, when we analyzed small subgroups of black andwhite women, who were matched by basal 25(OH)D levels,greater increments in resorption markers in response toPTH infusion were seen in white compared with blackwomen, with differences of very similar magnitude to thoseseen in the full groups. This again indicates that racialdifferences in basal vitamin D make at most a minor con-tribution to skeletal resistance to PTH in black women.Moreover, the concept of black skeletal physiology as an

adaptation from white physiology must be questioned, giventhe superior skeletal mass in blacks compared with whites.Adaptations in medical physiology do not usually overcom-pensate for the original condition that caused them tooccur. If PTH resistance developed only to preserve theskeleton, it is unlikely that the black skeleton could havebecome stronger than the white skeleton which did notrequire any adaptive changes in hormonal sensitivity.Therefore, it is likely that skeletal resistance to PTH is atleast partially independent of the relative vitamin D defi-ciency in black women.Racial differences in skeletal metabolism might be better

viewed in terms of white women’s physiology adapting fromthe black physiology. If white women were not as good atconserving calcium from extraskeletal sources (despite theirhigher mean vitamin D levels), they might have adapted byincreasing skeletal sensitivity to PTH to increase the cal-cium supply from the skeleton in order to maintain calciumhomeostasis. Preservation of skeletal mass might have beensacrificed in the process.In conclusion, if calcium homeostasis can be maintained

effectively in blacks through superior renal calcium conser-vation and perhaps increased gastrointestinal absorption(which has been seen in only one(22) of several stud-ies,(21,48,49) with less calcium liberation from skeletal tissue,higher bone mass could be maintained. These racial differ-ences in skeletal and mineral metabolism might thereforeexplain, at least in part, the lower incidence of osteoporosisin black women.

ACKNOWLEDGMENTS

This work was supported in part by National Institutes ofHealth grants AR41386 and DK46381 and AR39191.

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Address reprint requests to:Dr. Felicia Cosman

Regional Bone CenterHelen Hayes Hospital

West Haverstraw, NY 10993 U.S.A.

Received in original form November 27, 1996; in revised formJanuary 27, 1997; accepted February 6, 1997.

966 COSMAN ET AL.