Familial Resemblance of Bone Mineral Density (BMD) and Calcaneal Ultrasound Attenuation: The BMD in Mothers and Daughters Study†
Parts of this work were presented at the 18th Annual Meeting of the American Society for Bone and Mineral Research in Seattle, WA, U.S.A., 1996, and at the 29th Annual Meeting of the Society for Epidemiologic Research in Boston, MA, U.S.A., 1996.
The familial resemblance in bone mineral density (BMD) and calcaneal broadband ultrasound attenuation (BUA) was examined in 207 mother-daughter pairs. Mothers were participants in the Study of Osteoporotic Fractures. Three groups of daughters were recruited based on their maternal history of “fracture,” “low BMD” without fracture (< 0.58 g/cm2, t-score < −2.5), and “normal BMD” without fracture (> 0.67 g/cm2, t-score > −1.6). Data on other potentially heritable factors known to influence BMD and BUA were also collected. BMD was measured at the hip, spine, whole body, and calcaneus. Calcaneal BUA was assessed using the Walker-Sonix UBA 575. Total hip and femoral neck BMD were significantly lower (5.0–8.0%, p < 0.017) among daughters, in particular premenopausal daughters, of mothers with established osteoporosis (“fracture” or “low BMD”) compared with daughters of mothers at lower risk of osteoporosis (“normal BMD”). BUA did not differ across daughter groups. Lifestyle characteristics (dietary calcium, smoking, physical activity) were not highly correlated in mothers and daughters. Height, weight, and body composition were significantly correlated within mother-daughter pairs and could be a potential mechanism by which BMD is inherited. Among pre- and postmenopausal daughters, heritability estimates ranged from 50–63% and 34–48%, respectively. Heritability for calcaneal BUA (53%) was evident among postmenopausal daughters only. In conclusion, familial association in BMD was strongest among premenopausal daughters. Estimates of heritability suggest that maternal BMD and BUA are important independent predictors of BMD and BUA among daughters, reinforcing the importance of prevention and early intervention among women with a positive family history of osteoporosis. (J Bone Miner Res 1999;14: 102–110)
Osteoporosis is a significant public health problem accounting for 1.5 million fractures annually in the U.S. alone, at an annual cost of nearly $14 billion.(1,2) Identification of women at risk for osteoporosis is a major focus of research to target preventive strategies. Low bone mass is associated with increased risk of fracture but is considered a necessary, not a sufficient, predisposing factor.(3)
Previous studies have reported significant and relatively consistent parent–offspring correlations in bone mineral density (BMD) (4-14) and have shown that a family history of osteoporosis and/or fracture is associated with an increased risk of low BMD and fracture.(14-19) Some, (14,16) but not all,(6,13,17-19) of these studies confirmed a family history of osteoporosis or fracture via medical records or radiographs. Only a few studies have addressed the potential influence of “heritable” lifestyle factors on familial association in bone mass.(5,7,10) Nearly half of the studies limited BMD measurements to one key skeletal site(13,16,20) or failed to examine those sites that are most susceptible to disabling and catastrophic fracture, namely the hip and spine.(4,6,10,12,21,22) Furthermore, little is known about the heritability of quantitative ultrasound (QUS) parameters of bone, one of which, broadband ultrasound attenuation (BUA), has been shown to be predictive of fracture independent of BMD.(23,24) QUS parameters may reflect qualitative and architectural properties of bone separate from BMD which may have different modes of inheritance.
The aims of the present study were to examine the familial resemblance in BMD at several skeletal sites and calcaneal BUA, in addition to lifestyle and anthropometric characteristics, in a well-defined mother-daughter sample to test the following hypotheses: daughters of mothers with established osteoporosis will have lower BMD and BUA compared with daughters of mothers at lower risk for osteoporosis; mother-daughter BMD and BUA will be correlated; lifestyle and anthropometric characteristics known to influence BMD and BUA will be positively correlated within mother-daughter pairs; and mother BMD and BUA will be significant predictors of daughter BMD and BUA, respectively, after controlling for other factors known to influence bone mass.
MATERIALS AND METHODS
The Bone Mineral Density in Mothers and Daughters Study recruited 270 daughters, age range 30–70 years, of 207 mothers who were participants in the ongoing Study of Osteoporotic Fractures (SOF) at the Pittsburgh field center. SOF is a prospective, multicenter study of predictors of fracture in women, 65 years of age and older, from four clinical centers in the U.S. Details of SOF recruitment and methods are presented elsewhere.(25)
Daughters of SOF women were recruited via mailings and telephone contacts and placed into one of three groups based on their mother's history of fracture or level of BMD. One group consisted of daughters whose mothers had established osteoporosis as defined by an incident fracture of the hip, radius/ulna, or humerus during the first 5 years of follow-up in SOF or who had a prevalent vertebral deformity at baseline (“fracture” mothers). Prevalent deformity was defined as having a vertebral height ratio (anterior to posterior, mid- to posterior, or posterior to that of adjacent vertebra) on any vertebra (T5–L4) > 3 SD below the mean ratio at that vertebral level for the SOF cohort.(26)
A second group included daughters whose mothers were also osteoporotic as defined by low femoral neck BMD (“low BMD” mothers, < 0.58 g/cm2, t-score < −2.5, NHANES III reference data provided by the manufacturer(27) ) but who did not have a fracture during 5 years of follow-up in SOF.
Finally, a third group of daughters was recruited whose mothers were considered at lower risk of osteoporosis because of their normal BMD (“normal BMD” mothers, > 0.67 g/cm2, t-score > −1.6, NHANES III reference data provided by the manufacturer(27) ) and absence of fracture during 5 years of follow-up in SOF.
SOF women who were eligible for The Bone Mineral Density in Mothers and Daughters Study were similar to the general SOF population at the Pittsburgh field center with regard to age, body composition, and other lifestyle characteristics (data not shown). Forty-eight percent of daughters failed to respond to the initial mailing or refused participation, and the response rate did not vary across comparison groups. We excluded daughters who were pregnant or breastfeeding. All of the measurements in the daughter study followed the SOF protocol. The protocol was approved by the Biomedical Institutional Review Board at the University of Pittsburgh, and all daughters gave written informed consent. If more than one daughter per mother was recruited, randomly selected singleton daughters were used for the current analysis (n = 207 mother-daughter pairs).
A self-administered questionnaire was completed prior to the clinic exam, which assessed demographic, menstrual, and lifestyle characteristics. Physical activity during the previous 12 months was assessed using a modification of the Harvard Alumni survey.(28) Participants were asked to report the frequency of participation in 33 sport and recreational activities ranging from low (e.g., walking and bowling) to high (e.g., rope jumping and jogging/running) intensity. The activity frequencies were then intensity-weighted by their estimated energy cost (metabolic equivalents [METs]) and summed to create an index of weekly activity (METs/week). Lifetime smoking status was expressed as pack-years and calculated as the number of packs of cigarettes smoked daily multiplied by the total number of years of smoking.
Subjects who reported regular monthly menses were considered premenopausal. Premenopausal status was confirmed via a series of questions aimed at determining menstrual regularity. The ability to predict timing of menses and cycle length and absence of missed periods, oophorectomy, or hormone replacement therapy were used as indicators of premenopausal status. Postmenopausal subjects included those who reported an absence of natural menses for at least 12 months or who had undergone oophorectomy. Women reporting irregular menses during the previous 12 months and hysterectomized women reporting current estrogen replacement or who were 55 years of age or older were also classified as postmenopausal.
Daughters attended a clinic visit during which measurements of BMD, anthropometry, body composition, and muscular strength were made. Dual-energy X-ray absorptiometry (QDR 2000 array beam; Hologic, Waltham, MA, U.S.A.) was used to measure BMD of the hip, lumbar spine, and whole body. Single-energy X-ray absorptiometry (Osteoanalyzer; Dove Medical, Newbury Park, CA, U.S.A.) was used to measure calcaneal BMD. Coefficients of variation for the femoral neck, lumbar spine, and whole body were 1.3, 0.43, and 0.88%, respectively. Calcaneal BUA was measured using the Walker Sonix UBA 575 (Hologic) with a coefficient of variation of 5.0% in a short-term reproducibility study.(29) Whole-body BMD was not measured in the mothers.
A standard balance beam scale was used to measure current weight (kg) in lightweight clothing and without shoes. Height (cm) was measured without shoes using a wall-mounted Harpenden stadiometer (Holtain, Dyfed, U.K.). Bioelectrical impedance analysis (BIA) (Bio-Resistance Body Composition Analyzer; Valhalla Scientific, San Diego, CA, U.S.A.) was used to estimate fat-free mass (kg) and percentage body fat. Fat mass (kg) was calculated by multiplying the weight by percentage of body fat from BIA. Quadriceps strength was assessed using a isometric dynamometer (Bodymaster, Dublin, CA, U.S.A.) and the Jackson Evaluation System (Lafayette Instrument Co., Inc., Lafayette, IN, U.S.A.). Overall isometric quadriceps strength was calculated as the average of two maximum trials of isometric knee extension on each leg. Dietary calcium intake (mg/day) during the previous 12 months was assessed by an interviewer-administered, modified Block food frequency questionnaire. (30) Current use of estrogen replacement and calcium supplements was assessed during a medication interview.
Variables that were not normally distributed were either log transformed or nonparametrically tested. Chi-square tests were used for comparisons of categorical data. Differences across daughter groups in demographic, body composition, and lifestyle characteristics were assessed using analysis of variance, with Scheffe's test for pairwise comparisons of means or the Kruskal-Wallis test. Analysis of covariance was used to compare BMD and BUA across daughter groups, adjusting for age and weight. Analyses were initially conducted for the total population. We then stratified by menopausal status to test whether the association differed in each daughter group. Additional adjustment for current estrogen use was done for the postmenopausal daughter comparisons. At α = 0.05, the study had a power of 80% to detect a 0.50–1.0 SD difference in BMD across the daughter groups.
To define further osteoporotic risk in the daughters using standard criteria, daughters were considered at risk if their femoral neck BMD t-score was < −1, the World Health Organization cut point for osteopenia.(31) Chi-square analysis was used to test for differences in the proportion of pre- and postmenopausal daughters in the “fracture,” “low BMD,” and “normal BMD” groups who had a femoral neck BMD t-score of < −1.
Pearson product-moment or Spearman rank-order correlations were used to examine mother-daughter associations in BMD, BUA, lifestyle characteristics, anthropometrics, and body composition. Multiple regression analyses with backward elimination were used to examine heritability of BMD and BUA in pre- and postmenopausal daughters separately. Models included anthropometric and lifestyle characteristics that demonstrated a significant univariate association with daughter BMD and BUA along with mother's BMD or BUA, respectively. Twice the standardized beta coefficient of mother BMD or BUA from the multiple regression was used as an estimate of heritability. (32) Only those regression models in which the mother's BMD or BUA remained are presented in the tables. All statistical analyses were performed with SAS software (SAS Institute, Inc., Cary, NC, U.S.A.).
The mean age of daughters was 48.5 ± 7.3 years, with daughters in the “low BMD” group being significantly older than daughters of mothers with “fracture” (p < 0.05; Table 1). Daughter groups were similar with regard to anthropometrics, body composition, and lifestyle habits. The mean age of the mothers was 71.7 ± 4.6 years, with the “low BMD” mothers being significantly older (p < 0.05) than the “fracture” and “normal BMD” mothers (Table 1). “Normal BMD” mothers were significantly heavier and had more fat and fat-free mass than the osteoporotic mothers (p < 0.05). Lifestyle habits were generally similar across mother groups.
Table Table 1.. Descriptive Characteristics of Study Population (Mean ± SD)
BMD and BUA among daughters
Daughters in the “normal BMD” group had significantly greater (p < 0.017) age- and weight-adjusted total hip and femoral neck BMD than daughters in either of the osteoporotic groups, the differences approximating 0.5–0.75 SD in BMD (Table 2). These differences remained significant across premenopausal daughter groups only. In addition, a greater proportion of premenopausal daughters with a maternal history of osteoporosis had a BMD t-score < −1 as compared with daughters without such a history (47.6% and 36.0% for “fracture” and “low BMD” daughters, respectively, compared with 15.2% for “normal BMD” daughters; χ2 = 10.9, p = 0.004). Among postmenopausal daughters, BMD did not differ significantly across daughter groups, and there were no significant differences in the proportion of daughters in each group that had a t-score < −1 (“fracture” 50.0%, “low BMD” 56.2%, “normal BMD” 50.0%). However, postmenopausal daughters of women with “low BMD” had significantly lower BUA than daughters of women with “normal BMD” (p < 0.017).
Table Table 2.. Age- and Weight-Adjusted BMD (g/cm2) and BUA (dB/MHz) Across Daughter Groups, Total Population, and by Menopausal Status
Mother-daughter correlations in BMD and BUA
BMD was correlated in mothers and daughters (0.16 < r < 0.49), although the magnitude of the correlation was modest and more consistent among osteoporotic mothers and their daughters (Table 3). The familial correlation in BUA was only significant among “low BMD” mothers and their daughters.
Table Table 3.. Mother-Daughter Correlations in BMD (g/cm2), BUA (dB/MHz), Anthropometrics, and Lifestyle Characteristics Across Daughter Groups
Mother-daughter correlations in anthropometrics, body composition, and lifestyle
Anthropometrics and body composition were correlated in mothers and daughters across all daughter groups (Table 3). In contrast, we found little evidence that lifestyle characteristics were correlated in the mothers and daughters.
Estimates of heritability of BMD and BUA
Heritability estimates for BMD at the hip, spine, and calcaneus ranged from 50–63% among premenopausal daughters (Table 4). Among postmenopausal daughters, heritability estimates of 34% and 48% were observed only for the total hip and calcaneus, respectively (Table 5). Mother's BUA was predictive of daughter's BUA among postmenopausal daughters only with heritability estimated at 53% (Table 5).
Table Table 4.. Results of Regression Analyses and Estimates of Heritability of BMD (g/cm2) Among Premenopausal Daughters (n = 113)
Table Table 5.. Results of Regression Analyses and Estimates of Heritability of BMD (g/cm2) and BUA (dB/MHz) Among Postmenopausal Daughters (n = 94)
The findings of our study confirm the significance of heritability on bone mass and support the hypothesis that genetic influences on BMD may be stronger with regard to peak skeletal mass. We observed significant mother-daughter correlations in BMD, consistent with other parent-offspring studies,(4-14) which did not change substantially with adjustment for potential covariates, such as age and anthropometry. Daughters, particularly premenopausal daughters, of mothers with “normal BMD” had greater BMD at all sites than daughters of mothers who had established osteoporosis. The differences among premenopausal daughter groups were substantial, approaching a 1 SD difference in hip BMD. Lower BMD among the premenopausal daughters could translate to higher fracture risk in the future and certainly reinforces the need for prevention and early risk assessment, particularly among women with a positive family history. Our findings are consistent with several studies which compared bone mass among relatives with and without a family history of fracture or osteoporosis(6,14-17) but contrary to some others that found no increase in the prevalence of low bone mass,(5) vertebral deformity, (18) or fracture(33) among female offspring of women with osteoporotic fracture. Differences in sample selection, age of study participants, or fracture definition have been cited as possible reasons for the discrepant findings. Moreover, heritability estimates among premenopausal daughters in our study were comparable to those previously reported(4,6-7,20,22) and varied little by skeletal site, ranging from 50–63%. These findings have additional implications for prevention if heritability is not site specific for the premenopausal skeleton and may influence the choice of strategies to enhance the genetic potential of peak bone mass.
We found no difference in BMD among postmenopausal daughters. Furthermore, the heritability estimates were slightly lower among postmenopausal daughters. These findings reflect the multifactorial etiology of bone loss, possibly obscuring or overriding genetic influences on peak skeletal mass, and support the theory that genetic factors may play a lesser role and environmental factors a greater role in determining bone mass with age,(22,34) particularly at sites differing in the proportion of trabecular and cortical bone composition.(35,36) Little is known about the genetic influence on rates of bone turnover. Twin studies of males and postmenopausal women have both supported(35,37) and refuted(38,39) a significant genetic effect on bone turnover, but further studies are needed to better define the role of genetics in bone loss. Additionally, more research aimed at examining heritability as a function of age and menopausal status at multiple skeletal sites is warranted to better understand the full spectrum of heritability of bone mass throughout the skeleton and across the lifespan.
A proportion of the heritability of BMD observed in families is probably attributable to the familiality of lifestyle and environmental factors known to influence bone mass and osteoporosis risk. Several lifestyle behaviors have been shown to aggregate in families, including smoking,(40) alcohol intake,(10,41) lifetime milk consumption,(40) and physical activity.(40,42) However, we observed weak mother-daughter correlations in lifestyle characteristics, suggesting that the maternal influence on lifestyle factors did not contribute to the familial association in BMD among this sample of older women and their adult daughters.
In contrast, body composition and anthropometric measures were significantly correlated in mothers and daughters, consistent with previous reports of a genetic effect on body composition (lean and fat mass) and fat distribution,(43-47) body weight,(7) and height.(10,48) Hence, at least part of the familial association in BMD may reflect the heritability of body composition and anthropometry. The genes regulating body composition and BMD, however, may be the same(43,44) or different,(45,46) and research continues to explore the complex relationship between body composition and bone mass.
We found no consistent mother-daughter association in BUA across daughter groups. To our knowledge, there has only been one other published report examining the heritability of calcaneal BUA. Among postmenopausal twins there was a moderate genetic component to BUA and velocity of sound independent of BMD,(49) with heritability estimates of 0.45 and 0.58, respectively. Likewise, we found that the heritability of BUA was greater among postmenopausal daughters, suggesting that the familial effects on calcaneal microarchitecture may not be apparent until a later age or after menopause. Moreover, the magnitude of the heritability estimate was similar for calcaneal BMD and BUA among postmenopausal daughters. In contrast, there did not appear to be a significant heritable component to BUA among the premenopausal daughters. Overall, there were few predictors of BUA among the premenopausal daughters, and the correlation between calcaneal BMD and BUA was lower among premenopausal (r = 0.38) than postmenopausal (r = 0.63) daughters. This supports the hypothesis that single-energy X-ray absorptiometry and QUS measure different properties of bone that in the younger women may be subject to different familial influences. Alternatively, it may suggest that with age and/or menopause there is a more prominent shared heritable component to calcaneal BMD and BUA. Additional studies of the heritability of BUA, VOS, and other structural parameters are needed to clarify these issues.
The strengths of our study are that we recruited a well-defined mother-daughter sample, which is community based, and we have utilized two accepted classifications of established osteoporosis, namely incident fracture and low BMD. Since the heritability of fracture risk may include other mechanisms besides BMD, it is important to include both a BMD and fracture characterization of established osteoporosis when examining risk among offspring. Previous studies have not made that distinction. Finally, we were able to examine the heritability of BUA, a bone parameter shown to be an important independent predictor of fracture in women.
There are a number of limitations to our study. SOF women and their daughters represent a healthy, volunteer sample which may limit the generalizability of our findings. Although our sample size was sufficient to allow for comparisons across the three daughter groups, we were limited in statistical power when analyses were conducted in pre- and postmenopausal daughters separately. The range of duration of postmenopausal status among the postmenopausal daughters was quite broad (up to 33 years postmenopause) which could have resulted in considerable variability in bone mass, thus diluting any heritable effect on bone mass. We were unable to collect data on other family members, such as fathers and brothers. Finally, future studies should include analyses of specific genetic markers on these mother-daughter pairs.
In summary, we found that having a mother with low bone mass and/or osteoporotic fracture is associated with lower BMD, but not BUA, among daughters. The magnitude of the difference in BMD among premenopausal daughters was substantial, approaching 1 SD lower BMD, possibly leading to a higher risk of fracture in the future. Heritability estimates indicate that 34–63% of the variability in BMD may be attributed to inherited factors. Targeting daughters of women with osteoporosis at an early age may be warranted to reduce their risk of osteoporosis later in life.
This research was supported in part by the United States Public Health Service Research grants AR35582, T32AG00181, and AG05407.