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Calcium supplementation and bone fragility fractures during growth
International Congress Series 1297 (2007) 60 – 65
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Calcium supplementation and bone fragility fractures during growth A fracture risk assessment in a randomized controlled trial V. Matkovic a,⁎, J.D. Landoll a , N.E. Badenhop-Stevens a , E.-J. Ha c , Z. Crncevic-Orlic d , B. Li b , P.K. Goel b a Osteoporosis Prevention and Treatment Center and Bone and Mineral Metabolism Laboratory, Departments of Physical Medicine and Rehabilitation, Medicine, and Nutrition, Davis Medical Research Center, The Ohio State University, 480 W. 9th Av., Columbus, OH 43210, USA b Department of Statistics, The Ohio State University, Columbus, OH, USA c Department of Nutrition, Kent State University, Canton, OH, USA d Department of Endocrinology, Medical Faculty, University of Rijeka, Rijeka, Croatia
Abstract. It is known from short-term studies that calcium supplementation influences bone accretion during growth, but whether this has any implication with regard to fracture risk reduction is unknown. To address this issue, we have, therefore, evaluated the long-term effects of calcium supplementation (calcium citrate malate 1000 mg/day) on the prevalence of fractures in a cohort of young females, participants of a 7-year clinical trial. A total of 354 females were recruited to participate in a 4-year, randomized, double-blind, placebo-controlled clinical trial covering pubertal growth spurt, with subsequent extension for 3 years into late adolescence. Participants were accustomed to dietary calcium intake of ∼ 830 mg/day/7 years; supplemented individuals received additional ∼670 mg of calcium per day/7 years. Participants were asked to report on the fracture history at the end of the study, followed by the subsequent verification of the fracture data. Out of 26 verified fracture cases, 9 fracture cases were documented among the calcium-supplemented individuals, and 17 fractures were confirmed among the placebo individuals. Most fractures were at the forearm (50%) and occurred around the time of menarche. The Kaplan–Meier survival analysis showed a consistently lower rate of fractures among the calcium supplemented individuals, however,
⁎ Corresponding author. Tel.: +1 614 293 3819; fax: +1 614 293 4841. E-mail address: [email protected] (V. Matkovic). 0531-5131/ © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2006.08.009
V. Matkovic et al. / International Congress Series 1297 (2007) 60–65
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this was not statistically significant. The results of this study may be important for the design of a larger intervention trial with calcium supplementation with fracture as the main outcome. The results may have the ultimate implication with regard to the prevention of bone fragility during growth. © 2006 Elsevier B.V. All rights reserved. Keywords: Calcium; Calcium supplementation; Fracture; Growth; Bone mass
1. Introduction It was reported recently that calcium supplementation influences bone accretion trajectory from childhood to young adulthood [1]. This effect has been more pronounced during rapid skeletal modeling of pubertal growth spurt when calcium requirement is the highest of all the life span. Although the study was not designed to look into the bone fracture as the main outcome of the intervention, several children reported having fracture during the clinical trial, and more so in the placebo group with lower habitual calcium intake (∼ 830 mg/day) as compared to the calcium-supplemented individuals with calcium intake close to the threshold (∼ 1500 mg/day). Most of the fractures occurred around the time of menarche, or during the pubertal growth spurt [1], specific to the childhood fracture epidemiology [2–8]. Because of the nature of fractures in growing children (predominantly “green stick” type and sometime difficult to diagnose) relying on personal report for confirmation may not be enough. The purpose of the present study, therefore, was to verify the fracture status of the subjects from the clinical trial and to provide the fracture risk assessment among the cohort of young females as related to calcium intake. 2. Subjects and methods The study was conducted in a cohort of young females recruited from various school districts in central Ohio. The sample size calculation was based on the forearm bone mineral density measurements reported previously [9], as this was one of the primary outcome measures. The inclusion criteria were: Caucasian, normal health, pubertal stage 2, and calcium intake below the threshold level (1480 mg/day). This study was originally designed as a randomized, double-blind, 4-year controlled clinical trial, to assess the effect of calcium citrate–malate supplementation (1000 mg/day) on bone mineral density of the total body, radius, and metacarpal radiogrammetry of teenage females during the pubertal growth spurt. The study was subsequently extended for 3 more years into late adolescence with subjects who agreed to its continuation, while preserving the double-blind status. Fracture data were recorded by the end of the 7-year study, followed by the subsequent verification of the fracture status. For the purposes of the study, all fractures were included with the following exceptions: fractures not resulting from low to moderate trauma (e.g., motor vehicle accidents, falls from height) and fractures involving the phalanges (as these do not generally indicate bone fragility). The verification process was amended to the 7-year study protocol and approved by the Institutional Review Board at the O.S.U. The subjects were then contacted and permission obtained to conduct the record retrieval from the emergency departments, orthopedic surgeons, and pediatricians. Information concerning the fracture
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Fig. 1. Kaplan–Meier estimated fracture hazard for the 4-year cohort of young females. Calcium-supplemented individuals = solid line, placebo individuals = dotted line (p = 0.25).
and where the fracture was diagnosed was obtained. In some cases, (with the permission of the subjects) parents of the study participants were contacted to obtain information. When possible, primary X-ray, MRI, or bone scan reports read by radiologists were obtained. However, these were not always available, and other documentary evidence such as physician's notes, emergency department notes and orthopedist notes that report the fracture were obtained. In this clinical trial, the distribution of time until the subject experienced a fracture (fracture free time since menarche) was estimated by the Kaplan–Meier method. The S-plus 2000 package for Windows, Professional Release 3 (Insightful Corporation, Seattle, WA) was used for the statistical analyses. 3. Results Of the 29 subjects who reported having the fracture during the study, 28 were successfully contacted. One subject was “lost to follow-up” and her fracture information was not verified beyond her initial report. This subject was in the placebo arm of the study and reported that during the study she had sustained a broken ankle while playing basketball. Analysis of the records show that fractures during the study period are considered verified in 26 subjects, 1
Fig. 2. Kaplan–Meier estimated fracture hazard for the 7-year cohort of young females. Calcium-supplemented individuals = solid line, placebo individuals = dotted line (p = 0.27).
V. Matkovic et al. / International Congress Series 1297 (2007) 60–65
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Fig. 3. Kaplan–Meier estimated forearm fracture hazard for the 4-year cohort of young females. Calciumsupplemented individuals = solid line, placebo individuals = dotted line (p = 0.09).
subject did not sustain a fracture, and 1 subject sustained a fracture prior to entering the study (contrary to her initial report). Of the 26 verified fracture cases, 9 cases involved subjects who received supplementation with calcium and 17 occurred in subjects from the placebo group. Of the 26 cases, 13 involved forearm and 13 involved other bones (principally the foot and ankle). Considering the forearm fractures, 3 cases were from subjects in the calcium supplemented group with the remaining 10 cases from the placebo group. Cases involving locations other than the forearm were more evenly divided between the calcium supplemented (6 cases) and placebo (7 cases) groups. Of the 5 subjects who sustained foot/ankle fractures, only 1 was from the supplemented group. The average timing of the fracture was +1.2 ± 0.4 years since menarche, which coincides with the bone modeling phase in skeletal development and overlaps with the timing of the maximal effect of calcium supplementation on bone mineral density among young females in this study [1]. The results of the Kaplan–Meier estimated fracture hazard over time since menarche in the 4-year and 7-year cohorts are presented in Figs. 1 and 2 respectively. Figs. 3 and 4 present the Kaplan–Meier estimator for the forearm fracture hazard over time since menarche for the 4-year and 7-year cohorts, respectively. Based on the analysis, the calcium-supplemented individuals had a lower risk of fracture (forearm in particular), as
Fig. 4. Kaplan–Meier estimated forearm fracture hazard for the 7-year cohort of young females. Calciumsupplemented individuals = solid line, placebo individuals = dotted line (p = 0.10).
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V. Matkovic et al. / International Congress Series 1297 (2007) 60–65
compared to the placebo individuals; however, neither of the trends was statistically significant. 4. Discussion To what extent the bone fragility during growth is dependent on calcium intake is unknown and remains to be confirmed. Chan et al. [10] were the first to suggest that low dietary calcium intake might contribute to risk of bone fragility fractures in children, however, the results of the study were based on the dietary analysis in only a few cases. Lower calcium intakes and consumption of dairy products were documented in children with bone fragility fractures from New Zealand [11]. In a study in Palma de Mallorca, Spain, a significant difference in the fracture rate was found when cities with high calcium content in their water (282 mg/L) were compared with those with low calcium content (86 mg/L). With all other factors being equal (i.e., fluoride content, socioeconomic background), children who lived in the cities with lower calcium content in the drinking water had a higher fracture rate [12]. In another study, an increase in the consumption of carbonated beverages has been shown to produce an increased incidence of fractures in adolescents [13], most likely by displacing milk from the diet. The above studies provided additional supportive evidence; although far from being definitive, for the hypothesis of the relationship between Ca, bone mass, and fractures in children. Despite the fact that the fracture rate was not a primary research outcome in a 7-yearlong calcium supplementation trial [1], the reported fracture rate point in favor of calcium supplementation with regard to fracture risk reduction, although the sample size was too small for adequate interpretation. The predominance of fractures in the forearm, support the notion that this is a true bone fragility fracture during growth, as epidemiological data show [5]. As the peak incidence of bone fragility fracture coincides with the pubertal growth spurt [5–8], our results indicate that calcium intake at threshold level may reduce the risk of fracture during this stage of skeletal development characterized by bone deficiency [2,3], and irrespective of the catch-up phenomenon in bone mass acquisition occurring thereafter [1]. This is particularly important given the large number of childhood forearm fractures with rising incidence over the last 30 years [14]. A long-term intervention study with calcium supplementation in children, looking into the forearm fracture as the main research outcome, ought to be conducted to resolve this issue. Acknowledgements Supported by: NIH RO1 AR40736-01A1, CRC-NIH M01-RR00034, NRICGP/USDA37200-7586, Procter and Gamble Company, National Dairy Council. References [1] V. Matkovic, et al., Effects of calcium supplementation on bone mineral density of young females from childhood to young adulthood: a randomized clinical trial, Am. J. Clin. Nutr. 81 (2005) 175–188. [2] A.M. Parfitt, The two faces of growth: benefits and risks to bone integrity, Osteoporosis Int. 4 (1994) 382–398. [3] R.P. Heaney, et al., Peak bone mass, Osteoporosis Int. 11 (2000) 985–1009.
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[4] A.J. Buhr, A.M. Cooke, Fracture patterns, Lancet 1 (1959) 531–536. [5] P.A. Alffram, G.C.H. Bauer, Epidemiology of fractures of the forearm, J. Bone Jt. Surg. 44A (1962) 105–114. [6] W.M. Garraway, et al., Limb fractures in a defined population: I. Frequency and distribution, Mayo Clin. Proc. 54 (1979) 701–707. [7] D.A. Bailey, et al., Epidemiology of fractures of the distal end of the radius in children as associated with growth, J. Bone Jt. Surg. 71A (8) (1989) 125–130. [8] V. Matkovic, D. Klisovic, J.Z. Ilich, Epidemiology of fractures during growth and aging, Phys. Med. Rehabil. Clin. North Am. 6 (3) (1995) 415–439. [9] V. Matkovic, et al., Factors which influence peak bone mass formation: a study of calcium balance and the inheritance of bone mass in adolescent females, Am. J. Clin. Nutr. 52 (1990) 878–888. [10] G.M. Chan, et al., Bone mineral status in childhood accidental fractures, Am. J. Dis. Child. 138 (1984) 569–570. [11] A. Goulding, et al., Bone mineral density in girls with forearm fractures, J. Bone Miner. Res. 13 (1998) 143–148. [12] S. Verd Vellespir, et al., Asociacion entre el contenido en calcio de las aguas de consumo y las fracturas en los ninos, An. Esp. Pediatr. 37 (1992) 461–465. [13] G. Wyshak, R.E. Frisch, Carbonated beverages, dietary calcium, the dietary calcium/phosphorus ratio, and bone fractures in girls and boys, J. Adolesc. Health 15 (1994) 210–215. [14] S. Khosla, et al., Incidence of childhood distal forearm fractures over 30 years. A population-based study, JAMA 290 (2003) 1479–1485.
www.ics-elsevier.com
Calcium supplementation and bone fragility fractures during growth A fracture risk assessment in a randomized controlled trial V. Matkovic a,⁎, J.D. Landoll a , N.E. Badenhop-Stevens a , E.-J. Ha c , Z. Crncevic-Orlic d , B. Li b , P.K. Goel b a Osteoporosis Prevention and Treatment Center and Bone and Mineral Metabolism Laboratory, Departments of Physical Medicine and Rehabilitation, Medicine, and Nutrition, Davis Medical Research Center, The Ohio State University, 480 W. 9th Av., Columbus, OH 43210, USA b Department of Statistics, The Ohio State University, Columbus, OH, USA c Department of Nutrition, Kent State University, Canton, OH, USA d Department of Endocrinology, Medical Faculty, University of Rijeka, Rijeka, Croatia
Abstract. It is known from short-term studies that calcium supplementation influences bone accretion during growth, but whether this has any implication with regard to fracture risk reduction is unknown. To address this issue, we have, therefore, evaluated the long-term effects of calcium supplementation (calcium citrate malate 1000 mg/day) on the prevalence of fractures in a cohort of young females, participants of a 7-year clinical trial. A total of 354 females were recruited to participate in a 4-year, randomized, double-blind, placebo-controlled clinical trial covering pubertal growth spurt, with subsequent extension for 3 years into late adolescence. Participants were accustomed to dietary calcium intake of ∼ 830 mg/day/7 years; supplemented individuals received additional ∼670 mg of calcium per day/7 years. Participants were asked to report on the fracture history at the end of the study, followed by the subsequent verification of the fracture data. Out of 26 verified fracture cases, 9 fracture cases were documented among the calcium-supplemented individuals, and 17 fractures were confirmed among the placebo individuals. Most fractures were at the forearm (50%) and occurred around the time of menarche. The Kaplan–Meier survival analysis showed a consistently lower rate of fractures among the calcium supplemented individuals, however,
⁎ Corresponding author. Tel.: +1 614 293 3819; fax: +1 614 293 4841. E-mail address: [email protected] (V. Matkovic). 0531-5131/ © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2006.08.009
V. Matkovic et al. / International Congress Series 1297 (2007) 60–65
61
this was not statistically significant. The results of this study may be important for the design of a larger intervention trial with calcium supplementation with fracture as the main outcome. The results may have the ultimate implication with regard to the prevention of bone fragility during growth. © 2006 Elsevier B.V. All rights reserved. Keywords: Calcium; Calcium supplementation; Fracture; Growth; Bone mass
1. Introduction It was reported recently that calcium supplementation influences bone accretion trajectory from childhood to young adulthood [1]. This effect has been more pronounced during rapid skeletal modeling of pubertal growth spurt when calcium requirement is the highest of all the life span. Although the study was not designed to look into the bone fracture as the main outcome of the intervention, several children reported having fracture during the clinical trial, and more so in the placebo group with lower habitual calcium intake (∼ 830 mg/day) as compared to the calcium-supplemented individuals with calcium intake close to the threshold (∼ 1500 mg/day). Most of the fractures occurred around the time of menarche, or during the pubertal growth spurt [1], specific to the childhood fracture epidemiology [2–8]. Because of the nature of fractures in growing children (predominantly “green stick” type and sometime difficult to diagnose) relying on personal report for confirmation may not be enough. The purpose of the present study, therefore, was to verify the fracture status of the subjects from the clinical trial and to provide the fracture risk assessment among the cohort of young females as related to calcium intake. 2. Subjects and methods The study was conducted in a cohort of young females recruited from various school districts in central Ohio. The sample size calculation was based on the forearm bone mineral density measurements reported previously [9], as this was one of the primary outcome measures. The inclusion criteria were: Caucasian, normal health, pubertal stage 2, and calcium intake below the threshold level (1480 mg/day). This study was originally designed as a randomized, double-blind, 4-year controlled clinical trial, to assess the effect of calcium citrate–malate supplementation (1000 mg/day) on bone mineral density of the total body, radius, and metacarpal radiogrammetry of teenage females during the pubertal growth spurt. The study was subsequently extended for 3 more years into late adolescence with subjects who agreed to its continuation, while preserving the double-blind status. Fracture data were recorded by the end of the 7-year study, followed by the subsequent verification of the fracture status. For the purposes of the study, all fractures were included with the following exceptions: fractures not resulting from low to moderate trauma (e.g., motor vehicle accidents, falls from height) and fractures involving the phalanges (as these do not generally indicate bone fragility). The verification process was amended to the 7-year study protocol and approved by the Institutional Review Board at the O.S.U. The subjects were then contacted and permission obtained to conduct the record retrieval from the emergency departments, orthopedic surgeons, and pediatricians. Information concerning the fracture
62
V. Matkovic et al. / International Congress Series 1297 (2007) 60–65
Fig. 1. Kaplan–Meier estimated fracture hazard for the 4-year cohort of young females. Calcium-supplemented individuals = solid line, placebo individuals = dotted line (p = 0.25).
and where the fracture was diagnosed was obtained. In some cases, (with the permission of the subjects) parents of the study participants were contacted to obtain information. When possible, primary X-ray, MRI, or bone scan reports read by radiologists were obtained. However, these were not always available, and other documentary evidence such as physician's notes, emergency department notes and orthopedist notes that report the fracture were obtained. In this clinical trial, the distribution of time until the subject experienced a fracture (fracture free time since menarche) was estimated by the Kaplan–Meier method. The S-plus 2000 package for Windows, Professional Release 3 (Insightful Corporation, Seattle, WA) was used for the statistical analyses. 3. Results Of the 29 subjects who reported having the fracture during the study, 28 were successfully contacted. One subject was “lost to follow-up” and her fracture information was not verified beyond her initial report. This subject was in the placebo arm of the study and reported that during the study she had sustained a broken ankle while playing basketball. Analysis of the records show that fractures during the study period are considered verified in 26 subjects, 1
Fig. 2. Kaplan–Meier estimated fracture hazard for the 7-year cohort of young females. Calcium-supplemented individuals = solid line, placebo individuals = dotted line (p = 0.27).
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Fig. 3. Kaplan–Meier estimated forearm fracture hazard for the 4-year cohort of young females. Calciumsupplemented individuals = solid line, placebo individuals = dotted line (p = 0.09).
subject did not sustain a fracture, and 1 subject sustained a fracture prior to entering the study (contrary to her initial report). Of the 26 verified fracture cases, 9 cases involved subjects who received supplementation with calcium and 17 occurred in subjects from the placebo group. Of the 26 cases, 13 involved forearm and 13 involved other bones (principally the foot and ankle). Considering the forearm fractures, 3 cases were from subjects in the calcium supplemented group with the remaining 10 cases from the placebo group. Cases involving locations other than the forearm were more evenly divided between the calcium supplemented (6 cases) and placebo (7 cases) groups. Of the 5 subjects who sustained foot/ankle fractures, only 1 was from the supplemented group. The average timing of the fracture was +1.2 ± 0.4 years since menarche, which coincides with the bone modeling phase in skeletal development and overlaps with the timing of the maximal effect of calcium supplementation on bone mineral density among young females in this study [1]. The results of the Kaplan–Meier estimated fracture hazard over time since menarche in the 4-year and 7-year cohorts are presented in Figs. 1 and 2 respectively. Figs. 3 and 4 present the Kaplan–Meier estimator for the forearm fracture hazard over time since menarche for the 4-year and 7-year cohorts, respectively. Based on the analysis, the calcium-supplemented individuals had a lower risk of fracture (forearm in particular), as
Fig. 4. Kaplan–Meier estimated forearm fracture hazard for the 7-year cohort of young females. Calciumsupplemented individuals = solid line, placebo individuals = dotted line (p = 0.10).
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compared to the placebo individuals; however, neither of the trends was statistically significant. 4. Discussion To what extent the bone fragility during growth is dependent on calcium intake is unknown and remains to be confirmed. Chan et al. [10] were the first to suggest that low dietary calcium intake might contribute to risk of bone fragility fractures in children, however, the results of the study were based on the dietary analysis in only a few cases. Lower calcium intakes and consumption of dairy products were documented in children with bone fragility fractures from New Zealand [11]. In a study in Palma de Mallorca, Spain, a significant difference in the fracture rate was found when cities with high calcium content in their water (282 mg/L) were compared with those with low calcium content (86 mg/L). With all other factors being equal (i.e., fluoride content, socioeconomic background), children who lived in the cities with lower calcium content in the drinking water had a higher fracture rate [12]. In another study, an increase in the consumption of carbonated beverages has been shown to produce an increased incidence of fractures in adolescents [13], most likely by displacing milk from the diet. The above studies provided additional supportive evidence; although far from being definitive, for the hypothesis of the relationship between Ca, bone mass, and fractures in children. Despite the fact that the fracture rate was not a primary research outcome in a 7-yearlong calcium supplementation trial [1], the reported fracture rate point in favor of calcium supplementation with regard to fracture risk reduction, although the sample size was too small for adequate interpretation. The predominance of fractures in the forearm, support the notion that this is a true bone fragility fracture during growth, as epidemiological data show [5]. As the peak incidence of bone fragility fracture coincides with the pubertal growth spurt [5–8], our results indicate that calcium intake at threshold level may reduce the risk of fracture during this stage of skeletal development characterized by bone deficiency [2,3], and irrespective of the catch-up phenomenon in bone mass acquisition occurring thereafter [1]. This is particularly important given the large number of childhood forearm fractures with rising incidence over the last 30 years [14]. A long-term intervention study with calcium supplementation in children, looking into the forearm fracture as the main research outcome, ought to be conducted to resolve this issue. Acknowledgements Supported by: NIH RO1 AR40736-01A1, CRC-NIH M01-RR00034, NRICGP/USDA37200-7586, Procter and Gamble Company, National Dairy Council. References [1] V. Matkovic, et al., Effects of calcium supplementation on bone mineral density of young females from childhood to young adulthood: a randomized clinical trial, Am. J. Clin. Nutr. 81 (2005) 175–188. [2] A.M. Parfitt, The two faces of growth: benefits and risks to bone integrity, Osteoporosis Int. 4 (1994) 382–398. [3] R.P. Heaney, et al., Peak bone mass, Osteoporosis Int. 11 (2000) 985–1009.
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[4] A.J. Buhr, A.M. Cooke, Fracture patterns, Lancet 1 (1959) 531–536. [5] P.A. Alffram, G.C.H. Bauer, Epidemiology of fractures of the forearm, J. Bone Jt. Surg. 44A (1962) 105–114. [6] W.M. Garraway, et al., Limb fractures in a defined population: I. Frequency and distribution, Mayo Clin. Proc. 54 (1979) 701–707. [7] D.A. Bailey, et al., Epidemiology of fractures of the distal end of the radius in children as associated with growth, J. Bone Jt. Surg. 71A (8) (1989) 125–130. [8] V. Matkovic, D. Klisovic, J.Z. Ilich, Epidemiology of fractures during growth and aging, Phys. Med. Rehabil. Clin. North Am. 6 (3) (1995) 415–439. [9] V. Matkovic, et al., Factors which influence peak bone mass formation: a study of calcium balance and the inheritance of bone mass in adolescent females, Am. J. Clin. Nutr. 52 (1990) 878–888. [10] G.M. Chan, et al., Bone mineral status in childhood accidental fractures, Am. J. Dis. Child. 138 (1984) 569–570. [11] A. Goulding, et al., Bone mineral density in girls with forearm fractures, J. Bone Miner. Res. 13 (1998) 143–148. [12] S. Verd Vellespir, et al., Asociacion entre el contenido en calcio de las aguas de consumo y las fracturas en los ninos, An. Esp. Pediatr. 37 (1992) 461–465. [13] G. Wyshak, R.E. Frisch, Carbonated beverages, dietary calcium, the dietary calcium/phosphorus ratio, and bone fractures in girls and boys, J. Adolesc. Health 15 (1994) 210–215. [14] S. Khosla, et al., Incidence of childhood distal forearm fractures over 30 years. A population-based study, JAMA 290 (2003) 1479–1485.