ORIGINAL E n d o c r i n e

ARTICLE C a r e

The Effect of Nutritional Rickets on Bone Mineral Density Tom D. Thacher, Philip R. Fischer, and John M. Pettifor Department of Family Medicine (T.D.T.), Department of Pediatric and Adolescent Medicine (P.R.F.), Mayo Clinic, Rochester, Minnesota 55905; and MRC/Wits Developmental Pathways for Health Research Unit (J.M.P.), Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Parktown 2193, South Africa

Context: Nutritional rickets is caused by impaired mineralization of growing bone. The effect of nutritional rickets on areal bone mineral density (aBMD) has not been established. Objective: Our objective was to determine if aBMD is lower in children with active rickets than in healthy control children. We expected that the reduction in aBMD would vary between the radial and ulnar metaphyses near the growth plates and the proximal diaphyses. Design: Case-control study. Setting: Primary care outpatient department of a teaching hospital in Jos, Nigeria. Participants: Nigerian children with radiographically-confirmed rickets were compared with a reference group of control children without rickets from the same community. Main Outcome Measures: Forearm bone density measurements were performed in all children with pDXA. Age, sex, and height-adjusted bone density parameters were compared between children with rickets and control subjects. Results: A total of 264 children with active rickets (ages 13–120 months) and 660 control children (ages 11–123 months) were included. In multivariate analyses controlling for height, age, and gender, rickets was associated with a 4% greater bone area and 7% lower aBMD of the radial and ulnar metaphyses compared with controls (P ⬍ .001). The effects of rickets on the diaphyses of the radius and ulna were more pronounced with an 11% greater bone area, 21% lower aBMD, and 24% lower bone mineral apparent density than controls (P ⬍ .001). In children with rickets, aBMD values were unrelated to dairy product intake or serum calcium, phosphorus, alkaline phosphatase, or 25-hydroxyvitamin D. Metaphyseal aBMD was positively associated with radiographic severity score, attributed to bone edge detection artifact by densitometry in active rickets. Conclusion: Rickets results in increased bone area and reduced aBMD, which are more pronounced in the diaphyseal than in the metaphyseal regions of the radius and ulna, consistent with secondary hyperparathyroidism, generalized osteoid expansion and impaired mineralization. (J Clin Endocrinol Metab 99: 4174 – 4180, 2014)

N

utritional rickets is a deforming bone disease caused by impaired mineralization of growing bones, due to inadequate vitamin D or calcium. Ade-

quate concentrations of calcium and phosphorus at the growth plate are necessary for hydroxyapatite crystal formation, and phosphorus is further required for nor-

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received April 17, 2014. Accepted July 9, 2014. First Published Online July 25, 2014

Abbreviations: aBMD, areal BMD; BMAD, bone mineral apparent density; BMC, bone mineral content; BMD, bone mineral density; LC-MS/MS, liquid chromatography tandem mass spectrometry.

4174

jcem.endojournals.org

J Clin Endocrinol Metab, November 2014, 99(11):4174 – 4180

doi: 10.1210/jc.2014-2092

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 January 2015. at 04:21 For personal use only. No other uses without permission. . All rights reserved.

doi: 10.1210/jc.2014-2092

mal chondrocyte apoptosis. Nutritional rickets in most Nigerian children is due to inadequate dietary calcium intake, sometimes associated with suboptimal vitamin D status (1, 2). The diagnosis of rickets is principally based on radiographic evidence of widening of the growth plate with impaired mineralization. The radiographic consequences of rickets are most apparent at the rapidly expanding growth plates of the long bones, including the distal radius and ulna of the forearm. The radiographic appearance of rickets includes widening of the growth plates and fraying of the metaphyses, which allows for the assessment of the severity of rickets radiographically (3). Nutritional rickets and vitamin D deficiency have been associated with radiographic osteopenia (4), as a consequence of increased unmineralized osteoid and bone resorption. Thus, children with rickets would be expected to have reduced bone mineral density (BMD), but the effect of nutritional rickets on areal BMD (aBMD) has not been established. The aim of this study was to determine if aBMD is lower in children with nutritional rickets than in healthy control children. A secondary aim was to determine if a reduction in aBMD in children with rickets is more pronounced at the metaphysis of the distal forearm near the growth plate than in the more proximal forearm diaphysis.

Materials and Methods This case-control study was performed at the Jos University Teaching Hospital in the West African country of Nigeria, the most populous country in Africa. The teaching hospital is located in the city of Jos, about 10° north of the equator. Study subjects were children with rickets who had been enrolled in six clinical studies of nutritional rickets (5, 6) (and unpublished data) and had had a forearm bone density measurement at baseline, prior to treatment of rickets. Children with rickets in this study presented with clinical symptoms and signs suggestive of rickets. Active rickets was confirmed in all subjects with radiographs of the wrists and knees, based on a radiographic severity score greater than 1.5 on a 10-point scale, where 10 represents the greatest severity (3). Control subjects were healthy Nigerian children from the same community who had rickets excluded based on normal radiographs of the wrists and knees. Control children included 647 who had been enrolled in a trial of calcium supplementation to prevent rickets (7) and 13 who had been enrolled in a study of calcium absorption (5). The children in the calcium supplementation trial were enrolled between the ages of 12 and 18 months and received either calcium (approximately 500 mg daily as ground fish or calcium tablets) for 18 months or placebo. After completing the trial, this cohort had annual forearm bone density measurements until the age of 9 years. The effect of calcium supplementation on bone density was marginal and did not persist after discontinuation of calcium supplementation (8). Therefore we used all groups as our control group for this study. This cohort was divided into subgroups that represented all age

jcem.endojournals.org

4175

Figure 1. A, Forearm DXA measurement sites. B, Effect of metaphyseal calcification front on the detection of bone edge by DXA in rickets.

groups from 1 to 9 years. Each control subject had only one bone density measurement represented in the data set for analysis. In children who were given supplemental calcium during the trial, we used bone density data from 267 subjects obtained while on calcium supplementation (ages 12–36 months) and from 170 subjects obtained one year or more after completing calcium supplementation (age ⬎ 42 months). aBMD was measured in the left forearm with dual energy x-ray absorptiometry at the distal and proximal 1/3 radius and ulna by a single investigator (T.D.T.) with a portable densitometer (pDEXA, Model 476A110, Norland Medical Systems, Inc). The distal site is located at the site of minimal bone density proximal to the detected distal bone edge, representing the metaphyseal bone density of the radius and ulna (Figure 1A). This site is 1 cm in longitudinal width and identified by a preliminary rapid scout scan. The proximal 1/3 site is located at 1/3 the distance from the wrist to the elbow and represents diaphyseal bone density of the radius and ulna. Duplicate scans in 37 healthy control children demonstrated short-term in vivo precision of areal bone density of 0.007 g/cm2 (6.4%) at the distal radius and ulna and 0.013 g/cm2 (7.2%) at the proximal 1/3 radius and ulna (9). Long-term in vitro precision of areal bone density, assessed with a bone phantom, was 0.11 g/cm2 (1.1%). Serum biochemical values were available for a subset of children with rickets and control children at the time of bone density measurement. Blood was collected by venipuncture, and serum was stored at ⫺20°C until transported frozen to the Mayo Clinic. Serum calcium, phosphorus, alkaline phosphatase, and albumin were determined by standard methods. Concentrations of 25hydroxyvitamin D were measured by radioimmunoassay (DiaSorin) or by isotope-dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) (10). Written informed consent was obtained from a parent or guardian of all study subjects. Ethical approval for the study was obtained from the Jos University Teaching Hospital Ethical

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 January 2015. at 04:21 For personal use only. No other uses without permission. . All rights reserved.

4176

Thacher et al

Table 1.

Bone Density in Nutritional Rickets

J Clin Endocrinol Metab, November 2014, 99(11):4174 – 4180

Characteristics of Study Subjectsa

Characteristic Age (months) Female gender Religion (Christianity/Islam) Dairy product calcium intake (mg/d)c Age weaned from breast (months) Age started walking (months) Radiographic score Anthropometric characteristics Height for age z-score Weight for age z-score Weight for height z-score Serum Biochemistry Calcium (mg/dL) Albumin (g/dL) Phosphorus (mg/dL) Alkaline phosphatase (U/L) 25-hydroxyvitamin D (ng/mL) Bone Densitometryd Distal radius and ulna BMC (g) Bone area (cm2) Areal BMD (g/cm2) Areal BMD z-score BMAD (g/cm3) Proximal 1/3 radius and ulna BMC (g) Bone area (cm2) Areal BMD (g/cm2) Areal BMD z-score BMAD (g/cm3)

Children With Rickets (n ⴝ 264)

Control Children (n ⴝ 660)

40 (13–120) 154 (58%) 150/114 20 (0 – 442) 18 (1–36) (n ⫽ 240) 15 (6 – 60) (n ⫽ 218) 5.6 ⫾ 2.3

33 (11–123) 331 (50%) 121/539 0 (0 – 855) 19 (2–26) (n ⫽ 471) 13 (7–26) (n ⫽ 544) 0

⬍.001

⫺3.5 ⫾ 1.6 ⫺2.8 ⫾ 1.8 ⫺0.3 ⫾ 1.1

⫺1.7 ⫾ 1.4 ⫺1.9 ⫾ 1.5 ⫺0.7 ⫾ 1.4

⬍.001 ⬍.001 ⬍.001

8.4 ⫾ 1.3 (n ⫽ 155) 4.3 ⫾ 0.6 (n ⫽ 143) 3.4 ⫾ 1.0 (n ⫽ 152) 568 (182– 4622) (n ⫽ 152) 14 (2–36) (n ⫽ 190)

9.8 ⫾ 0.6 (n ⫽ 450) 4.0 ⫾ 0.4 (n ⫽ 448) 5.4 ⫾ 0.8 (n ⫽ 351) 219 (51–1395) (n ⫽ 448) 20 (3–51) (n ⫽ 257)

⬍.001

0.272 ⫾ 0.106 2.055 ⫾ 0.373 0.130 ⫾ 0.036 ⫺0.782 ⫾ 1.362 0.091 ⫾ 0.024

0.313 ⫾ 0.153 2.010 ⫾ 0.385 0.149 ⫾ 0.044 Referencee 0.105 ⫾ 0.023

⬍.001 .12 ⬍.001 ⬍.001 ⬍.001

0.361 ⫾ 0.117 1.870 ⫾ 0.234 0.191 ⫾ 0.046 ⫺1.530 ⫾ 1.128 0.140 ⫾ 0.031

0.448 ⫾ 0.223 1.722 ⫾ 0.230 0.252 ⫾ 0.095 Referencee 0.190 ⫾ 0.063

⬍.001 ⬍.001 ⬍.001 ⬍.001 ⬍.001

P Valueb ⬍.001 .03 ⬍.001 ⬍.001 .03 ⬍.001

⬍.001 ⬍.001 ⬍.001 ⬍.001

Normally distributed data are shown as means ⫾ SD Non-normally distributed data are shown as median (range). When the data for the entire group were not available, subgroup sizes are indicated.

a

b c

P values were determined by the t-test for normally distributed data and by the Mann-Whitney test for non-normally distributed data.

Excludes breast milk intake.

d

BMC ⫽ bone mineral content; BMD ⫽ bone mineral density; BMAD ⫽ bone mineral apparent density.

e

Z-scores for bone density used the control children as the reference group, which by definition have a mean of zero and standard deviation of 1.0.

Committee and from the Mayo Clinic Institutional Review Board. Statistical analyses were performed with JMP 9.0.1 (SAS Institute). A standard least squares multivariate model was used to determine the significance of differences in bone density parameters between case and control subjects and to control for the effects of age, sex, and height in adjusted analyses. Anthropometric weight for height and height for age z-scores were calculated using the nutrition program of Epi Info 3.5.4 (CDC), using the 2000 CDC Growth Reference Charts. Two-tailed P values ⬍ .05 were considered significant. As a measure to correct for the volumetric effect of bone size on aBMD, bone mineral apparent density (BMAD) was calculated by dividing the bone mineral content (BMC) by the bone area raised to the power of 1.5 (11). Bone mineral density standard z-scores were calculated based on

using the control group as a population reference in one-year age increments.

Results We studied 264 children with nutritional rickets (ages 13– 120 months) and 660 control subjects (ages 11–123 months). Control children differed from children with rickets, because they were not selected in the same manner. Compared with control subjects, children with rickets were slightly older, had reduced height for age in part due to their leg deformities, and had a slightly greater weight

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 January 2015. at 04:21 For personal use only. No other uses without permission. . All rights reserved.

doi: 10.1210/jc.2014-2092

Figure 2. Age distribution of study subjects.

for height (Table 1). A greater proportion of control children were under 2 years of age and over 7 years of age than were children with rickets (Figure 2). Compared to control subjects, children with rickets had lower serum 25-hydroxyvitamin D, calcium, and phosphorus values and higher serum alkaline phosphatase, as expected in nutritional rickets. Of those tested, 79 children (42%) with rickets and 19 control children (7%; P ⬍ .001) had vitamin D deficiency (25-hydroxyvitamin D ⱕ 12 ng/mL). In controls, aBMD increased linearly in the metaphysis (r ⫽ 0.83) and diaphysis (r ⫽ 0.90) with age (P ⬍ .001, Figure 3). This relationship of aBMD with age was less evident at the metaphysis (r ⫽ 0.38) and diaphysis (r ⫽ 0.54) of children with rickets. In the least squares regression model of aBMD at the metaphysis, the parameter

Figure 3. Relationship of aBMD of the proximal 1/3 radius and ulna diaphyses with age in 264 children with rickets and 660 healthy control children. Calcium supplemented control children (n ⫽ 437) received calcium for 18 months prior to age 3 years.

jcem.endojournals.org

4177

estimates for age (0.0135 g/cm2/y) and the presence of rickets (⫺0.0097 g/cm2) were both significant (P ⬍ .001). In the model of aBMD at the diaphysis, the parameter estimates for age (0.0314 g/cm2/y) and the presence of rickets (⫺0.0336 g/cm2) were also both significant (P ⬍ .001). The interaction of age with the presence of rickets was significant (P ⬍ .001) at both the metaphysis and diaphysis, indicating greater divergence of aBMD with advancing age between children with rickets and control children (Figure 3). BMC was exponentially related to height in both children with rickets and control children. BMC in g ⫽ Ae0.02⫻height in cm, with the constant A equal to 0.05 at the metaphysis and ranging from 0.06 (controls) to 0.07 (rickets) at the diaphysis. This formula explained 78% and 81% (R2) of the variation in metaphyseal and diaphyseal BMC, respectively, in control children. Greater unexplained variance in the relationship of BMC with height in children with rickets resulted in R2 values of 30% and 37% for the metaphyseal and diaphyseal BMC, respectively, in children with rickets. Based on least squares mean values adjusted for age, height, and gender, nutritional rickets was associated with a 4% greater metaphyseal bone area and 7% lower aBMD and BMC compared with controls (P ⬍ .001, Figure 4). BMAD was 8% lower in children with rickets than in control subjects, indicating that volumetric correction of aBMD did not substantially alter the results. The adjusted mean z-score of the metaphyseal aBMD in children with rickets was ⫺0.78 ⫾ 1.36. Unexpectedly, the effects of rickets on the diaphyseal bone of the proximal 1/3 radius and ulna were even more pronounced than at the distal site. Compared with control children, bone area was 11% greater, BMC was 14% lower, and aBMD was 21% lower in children with rickets in the adjusted analysis (P ⬍ .001, Figure 5). The BMAD was 24% lower in children with rickets than in control subjects. Compared with control subjects, the adjusted mean diaphyseal aBMD z-score was lower in children with rickets (⫺1.53 ⫾ 1.13), with a greater difference with advancing age. In children with rickets, metaphyseal and diaphyseal aBMD values were unrelated to dairy product calcium intake or serum values of calcium, phosphorus, alkaline phosphatase, or 25-hydroxyvitamin D. Unexpectedly, metaphyseal aBMD was positively associated with radio-

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 January 2015. at 04:21 For personal use only. No other uses without permission. . All rights reserved.

4178

Thacher et al

Bone Density in Nutritional Rickets

J Clin Endocrinol Metab, November 2014, 99(11):4174 – 4180

control subjects that had never received calcium supplements. At the diaphyseal site, nutritional rickets was associated with a 8% greater bone area, 14% lower BMC, and a 20% lower aBMD (P ⬍ .001 for all comparisons) than control children in the adjusted analysis.

Discussion Nutritional rickets results in increased bone area and reduced aBMD, the effects of which are more pronounced in the diaphyseal than in the metaphyseal regions of the radius and ulna. These findings were also confirmed with volFigure 4. Comparison of bone density parameters of the distal radius and ulna metaphyses in umetric correction using BMAD and children with rickets and healthy control children. Least squares mean values, adjusted for age, height, and gender, are shown above each bar. Error bars indicate the standard error of the standardized aBMD z-scores. Despite mean. the characteristic radiographic changes of rickets at the distal metaphyses at graphic severity score in the adjusted analysis. The in2 the wrist, the effect of rickets/osteomalacia on aBMD of the crease in aBMD (g/cm ) for each unit increase in radiodiaphyses was approximately three times greater than on the graphic score was 0.0027 (P ⫽ .01). This means that more severe rickets on radiographs was associated with in- metaphyses of the radius and ulna. The relative diaphyseal bone mineral deficit might be creased metaphyseal aBMD compared with those with less explained by the effect of increased parathyroid hormone severe rickets. Diaphyseal aBMD was unrelated to radioconcentrations, which are associated with nutritional graphic severity score. A sensitivity analysis that limited comparison with the rickets. Chronic hyperparathyroidism leads to increased 223 control subjects who had never received calcium sup- intracortical tunnelling and periosteal bone expansion, so plementation did not substantially alter our conclusions. it is possible that children with dietary calcium deficiency In the least squares analysis adjusted for age, height, and will have wider diaphyseal shafts due to cortical expangender, nutritional rickets was associated with a 2% sion. The latter was found in studies of children in Soweto greater metaphyseal bone area (P ⫽ .08), 9% lower aBMD and a rural area in South Africa (12). Additionally, during (P ⬍ .001), and 9% lower BMC (P ⫽ .002) compared with bone remodeling, bone resorption followed by replacement with unmineralized osteoid in the diaphyses could account for reduced aBMD, bowing of long bones, and fractures associated with rickets. It is also possible that the increased bone area and wider diaphyseal shafts predated the onset of rickets and were separate from any postulated changes in parathyroid hormone levels. The absence of FokI alleles of the vitamin D receptor gene (termed FF) is linked to rickets in children (13, 14) and, conversely, to greater bone density in some postmenopausal women (15). Children who are genetically predisposed to grow larger stronger bones are possibly more likely to develop rickets when exposed to inadequate intake of either vitamin D or calcium. Structural factors affecting pediatric bones and fracture risk are not Figure 5. Comparison of bone density parameters of the proximal 1/3 radius and ulna diaphyses in children with rickets and healthy control associated with fracture risk in older women (16). children. Least squares mean values, adjusted for age, height, and The surprising finding of an increase in metaphyseal gender, are shown above each bar. Error bars indicate the standard aBMD (but still lower than the controls) with increasing error of the mean.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 January 2015. at 04:21 For personal use only. No other uses without permission. . All rights reserved.

doi: 10.1210/jc.2014-2092

severity of radiographic rickets may be an artifact of bone edge detection by the densitometer. In young children with rickets, especially those without visible epiphyses of the radius and ulna, the distal bone edge is the mineralization front at the growth plate. With increasing severity of rickets, radiographs show increased distal metaphyseal cupping and fraying. This would result in more proximal identification of the distal bone edge by densitometry in severe rickets (Figure 1B), and bone density increases proximally with transition to diaphyseal bone. Several studies have reported normative values for aBMD in children. Zanchetta and colleagues reported an increase in radial aBMD in Caucasian children from 0.19 g/cm2 at age 2 years to 0.26 g/cm2 at age 9 years in males with similar values in females, which are comparable to the aBMD values of children with rickets in our study and less than those of control children (17). These differences may be due to ethnic differences in bone mass which have been reported by a number of researchers (18). African American children have higher aBMD than their white peers. Similar ethnic differences have been reported at the hip in South African children (19). Because rickets is associated with lower limb shortening in particular, the effect of adjusting for height in the analysis of bone density parameters results in children with rickets being compared with younger normal children, which could advantage the results in children with rickets. However, BMC is more closely related to height in both children with and without rickets than it is to age. Our results consistently showed lower aBMD in children with rickets than in control children, whether adjustment was based on age, height, or both variables simultaneously. One potential clinical implication of our findings is that diaphyseal bone may be more prone to fracture than the metaphysis in children with nutritional rickets, related to the greater effect of rickets on diaphyseal than metaphyseal aBMD. However, this may be partially compensated for by the increased bone diameter, which increases bone strength. With treatment of nutritional rickets, the mineralization deficit is potentially largely reversible. We have previously reported that during a 6-month interval of treatment for nutritional rickets, bone mineral content increased by 22–37% in both metaphyseal and diaphyseal sites of the radius and ulna (20). One of the strengths of our study is the large number of children with nutritional rickets who have bone density data. However, we did not measure volumetric bone density, which would have provided a more accurate measure of true bone density, and would have helped us to determine the degree of unmineralized osteoid in the diaphyseal cortex and of unmineralized cartilage in the metaphysis.

jcem.endojournals.org

4179

Additionally, the in vivo precision of DXA measurements was only determined in healthy control children and not in children with rickets. As with any case-control study, the effects of unmeasured confounders may have affected the results. However, given the magnitude and significance of the differences we found, which did not change with sensitivity analyses or inclusion of various variables in multivariate modeling, the measured effect of nutritional rickets on bone density appeared robust. We did not measure parathyroid hormone concentrations in most subjects, so the assumption that secondary hyperparathyroidism was related to the increase in diaphyseal diameter is unproven. We also did not measure fracture rates, so we were unable to assess the relationship of bone density with fracture rate in children with rickets. We conclude that nutritional rickets results in increased bone area and reduced aBMD, which are more pronounced in the diaphyseal than in the metaphyseal regions of the radius and ulna. The osteoid expansion and impaired mineralization may be more pronounced in cortical bone of the diaphyses than in the trabecular bone of the metaphyses.

Acknowledgments Address all correspondence and requests for reprints to: Tom D. Thacher, MD, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: [email protected]. This work was supported by the Thrasher Research Fund. Disclosure Summary: P.R.F. and J.M.P. have nothing to disclose. T.D.T. is a consultant for Biomedical Systems.

References 1. Thacher TD, Fischer PR, Pettifor JM, et al. A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children. N Engl J Med. 1999;341:563–568. 2. Thacher TD, Fischer PR, Obadofin MO, Levine MA, Singh RJ, Pettifor JM. Comparison of metabolism of vitamins D2 and D3 in children with nutritional rickets. J Bone Miner Res. 2010;25:1988 – 1995. 3. Thacher TD, Fischer PR, Pettifor JM, Lawson JO, Manaster BJ, Reading JC. Radiographic scoring method for the assessment of the severity of nutritional rickets. J Trop Pediatr. 2000;46:132–139. 4. Gordon CM, Feldman HA, Sinclair L, et al. Prevalence of vitamin D deficiency among healthy infants and toddlers. Arch Pediatr Adolesc Med. 2008;162:505–512. 5. Thacher TD, Aliu O, Griffin IJ, et al. Meals and dephytinization affect calcium and zinc absorption in Nigerian children with rickets. J Nutr. 2009;139:926 –932. 6. Thacher TD, Obadofin MO, O’Brien KO, Abrams SA. The effect of vitamin D2 and vitamin D3 on intestinal calcium absorption in Nigerian children with rickets. J Clin Endocrinol Metab. 2009;94: 3314 –3321. 7. Thacher TD, Fischer PR, Isichei CO, Zoakah AI, Pettifor JM. Prevention of nutritional rickets in Nigerian children with dietary calcium supplementation. Bone. 2012;50:1074 –1080.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 January 2015. at 04:21 For personal use only. No other uses without permission. . All rights reserved.

4180

Thacher et al

Bone Density in Nutritional Rickets

8. Umaretiya PJ, Thacher TD, Fischer PR, Cha SS, Pettifor JM. Bone mineral density in Nigerian children after discontinuation of calcium supplementation. Bone. 2013;55:64 – 68. 9. Glüer CC, Blake G, Lu Y, Blunt BA, Jergas M, Genant HK. Accurate assessment of precision errors: how to measure the reproducibility of bone densitometry techniques. Osteoporos Int. 1995;5:262–270. 10. Singh RJ. Quantitation of 25-OH-vitamin D (25OHD) using liquid tandem mass spectrometry (LC-MS-MS). Methods Mol Biol. 2010; 603:509 –517. 11. Carter DR, Bouxsein ML, Marcus R. New approaches for interpreting projected bone densitometry data. J Bone Miner Res. 1992; 7:137–145. 12. Pettifor JM, Moodley GP. Appendicular bone mass in children with a high prevalence of low dietary calcium intakes. J Bone Miner Res. 1997;12:1824 –1832. 13. Fischer PR, Thacher TD, Pettifor JM, Jorde LB, Eccleshall TR, Feldman D. Vitamin D receptor polymorphisms and nutritional rickets in Nigerian children. J Bone Miner Res. 2000;15:2206 –2210. 14. Mao S, Huang S. Vitamin D receptor gene polymorphisms and the risk of rickets among Asians: a meta-analysis. Arch Dis Child. 2014; 99:232–238. 15. Wang D, Liu R, Zhu H, Zhou D, Mei Q, Xu G. Vitamin D receptor

J Clin Endocrinol Metab, November 2014, 99(11):4174 – 4180

16.

17.

18.

19.

20.

Fok I polymorphism is associated with low bone mineral density in postmenopausal women: a meta-analysis focused on populations in Asian countries. Eur J Obstet Gynecol Reprod Biol. 2013;169:380 – 386. Amin S, Melton LJ 3rd, Achenbach SJ, et al. A distal forearm fracture in childhood is associated with an increased risk for future fragility fractures in adult men, but not women. J Bone Miner Res. 2013; 28:1751–1759. Zanchetta JR, Plotkin H, Alvarez Filgueira ML. Bone mass in children: normative values for the 2–20-year-old population. Bone. 1995;16:393S–399S. Zemel BS, Kalkwarf HJ, Gilsanz V, et al. Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study. J Clin Endocrinol Metab. 2011; 96:3160 –3169. Vidulich L, Norris SA, Cameron N, Pettifor JM. Differences in bone size and bone mass between black and white 10-year-old South African children. Osteoporos Int. 2006;17:433– 440. Thacher TD, Fischer PR, Pettifor JM.Vitamin D treatment in calcium-deficiency rickets: a randomised controlled trial [published online April 19, 2014]. Arch Dis Child. doi:10.1136/archischild2013-305275.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 January 2015. at 04:21 For personal use only. No other uses without permission. . All rights reserved.

The effect of nutritional rickets on bone mineral density.

Nutritional rickets is caused by impaired mineralization of growing bone. The effect of nutritional rickets on areal bone mineral density (aBMD) has n...
527KB Sizes 0 Downloads 7 Views