Diagnoses Among Children With High PTH and/or Phosphate Levels
Among the 50 children with high PTH and/or high phosphate, only 1 child had a relevant clinical diagnosis other than HIV (ie, chronic kidney disease). That child was included in all analyses. None of the PHEU children had a relevant diagnosis.
Association of 25(OH)D and PTH With Bone
Among PHIV children (Table 2), those with low 25(OH)D, compared with those without, had adjusted TB-BMD z-scores that were on average 0.38 SD lower [95% confidence interval (95% CI), −0.60 to −0.16] and TB-BMC levels that were 59.1 g lower (95% CI, −108.3 to −9.8). In an unadjusted analysis, this represents a 5.9% lower TB-BMC. Similar results were observed for TBLH-BMC. Among PHEU children, adjusted TB-BMD z-scores were on average 0.34 SD lower (95% CI, −0.64 to −0.03) in children with low 25(OH)D, but there were no differences in TB-BMC and TBLH-BMC. In models including PHIV and PHEU children, there was no strong indication of effect modification of HIV status by low 25(OH) for any of the bone outcomes (P > 0.29), but power may be limited.
The average adjusted difference in LS-BMD z-scores between those with versus without low 25(OH)D was −0.21 SD (95% CI, −0.42 to 0.0) for PHIV and 0.10 SD (95% CI, −0.30 to 0.51) for PHEU children. There were no differences in LS-BMC by 25(OH)D status in PHIV or PHEU children.
There was no apparent difference in any bone outcome by PTH status among PHIV children (Table 2). The average difference in TB-BMD z-scores was −0.02 (95% CI, −0.37 to 0.42) between those with high versus normal PTH. However, TB-BMD z-scores were on average 0.48 SD lower (95% CI, −0.92 to −0.03) in children with low 25(OH)D and high PTH and 0.28 SD units lower (95% CI, −0.51 to −0.05) in those with low 25(OH)D and normal PTH, compared with the reference group (25(OH)D > 20 ng/mL and PTH ≤ 65 pg/mL) (See Table, Supplemental Digital Content 1, http://links.lww.com/QAI/B45). LS-BMC was on average 3.1 g lower (95% CI, −6.2 to 0.05) in PHIV with low 25(OH)D and high PTH compared with the reference.
Differences in Characteristics by 25(OH)D and PTH Status in PHIV and PHEU Children
Characteristics associated with low 25(OH)D for PHIV and PHEU children combined included older age, female sex, black race, African ancestry, blood drawn in winter or spring, northern latitude, Tanner stage >1, higher percent body fat, lower calcium and phosphate, and higher PTH and creatinine (Table 3) (See Table, Supplemental Digital Content 2, http://links.lww.com/QAI/B45). Among the PHIV, children with low 25(OH)D had lower CD4 counts and were more likely to receive EFV.
Factors associated with high PTH were older age, African ancestry, Tanner stage >1, lower 25(OH)D and calcium, and higher creatinine. Among PHIV children, those with high PTH had a lower frequency of EFV use, a higher frequency of TDF use, and higher HIV viral load (Supplemental Digital Content 3, http://links.lww.com/QAI/B45) (48 of 401 received both TDF and EFV).
Prevalence of Low 25(OH)D in PHIV Compared With PHEU Children
The aPR (95% CI) of low 25(OH)D was 1.00 (0.81 to 1.24) in PHIV relative to PHEU children (Table 4, model 1B), 1.30 (0.98 to 1.74) in PHIV receiving EFV compared with PHEU children (model 2B), and 0.95 (0.76 to 1.18) in PHIV not receiving EFV compared with PHEU children (Table 4, model 2B). The opposite trend was observed for PHIV receiving TDF compared with PHEU (aPR, 0.77; 95% CI, 0.56 to 1.06, model 3B). Differences in mean 25(OH)D levels by HIV, and by EFV and TDF use, suggest similar results (Table 4, models 7B–9B).
Prevalence of High PTH in PHIV Compared With PHEU Children
PHIV had a 3.17 (1.25 to 8.06) times greater adjusted prevalence of high PTH than PHEU children (Table 4, model 4B). The average difference between groups was 5.26 pg/mL (2.35 to 8.17). PHIV who were not receiving EFV (Table 4, model 5B) had a 3.67 times higher prevalence of high PTH than PHEU children (1.44 to 9.36). The prevalence of high PTH (Table 4, model 6B) was 5.50 (1.95 to 15.49) times higher in PHIV receiving TDF compared with PHEU children and 2.64 times higher in PHIV not receiving TDF (1.01 to 6.94) than in PHEU children. Compared with PHEU, PTH concentrations were on average 5.54 pg/mL higher in PHIV not receiving EFV (Table 4, model 11B) and 11.65 pg/mL higher in those receiving TDF (Table 4, model 12B), compared with PHEU children.
Relationship Between Calcium and PTH by HIV Status and TDF Use
Serum calcium and PTH were negatively associated in PHIV not receiving TDF (slope, −10.5; P = 0.001) and PHEU (slope, −7.6; P = 0.002) but not associated among PHIV receiving TDF (slope, −3.8; P = 0.56) (See Figure, Supplemental Digital Content 4, http://links.lww.com/QAI/B45).
In this multicenter cohort of PHIV and PHEU children in the United States, 40% had vitamin D deficiency overall, and the prevalence did not differ by HIV status after careful adjustment for confounding. In both PHIV and PHEU children, low 25(OH)D was associated with lower TB-BMD but not with LS-BMD in either cohort. PTH levels were highest in PHIV children receiving TDF. Although PTH levels were, on average, higher in PHIV children with low 25(OH)D, high PTH was only associated with lower TB-BMD when accompanied by low 25(OH)D. The relationship between calcium and PTH was weak in PHIV children receiving TDF.
Several randomized clinical trials have been done examining the effects of vitamin D supplementation on healthy children and adolescents.24 A meta-analysis of 6 such randomized clinical trials found that children with normal baseline 25(OH)D concentrations (>18 ng/mL) did not have benefits in BMD accrual from supplementation but that there was a significant positive effect of supplementation on TB and a borderline significant effect on spine BMD among those with low levels of 25(OH)D at baseline.25 Four cross-sectional studies of the relationship of 25(OH)D as a continuous variable with BMD in normal children found positive associations with whole-body BMD,26–29 2 with LS,26,29 1 with total hip,29 and 1 with the forearm.28 No associations were found in 5 other cross-sectional studies.30–34 We previously found that TB-BMD was greater in PHIV children using vitamin supplements.35 In a study of vitamin D and calcium supplementation over 2 years in PHIV children, 25(OH)D levels increased, but this did not significantly increase TB or spine BMC or BMD measures over time.7 In the aforementioned study, those who advanced through puberty during the study period had a greater increase in TB-BMC and LS-BMC in the supplemented group, but this result did not achieve significance. Thus, our finding that low 25(OH)D was associated with decreased TB BMD and BMC is supported by some, but not all, studies. Because the effect sizes on BMD from vitamin D supplementation appear to be modest, and many prior studies have used low doses of vitamin D supplementation (as little as 133 IU/day) and included children who at baseline were vitamin D replete, further adequately powered studies examining the effects of vitamin D supplementation to target adequate 25(OH)D serum concentrations across puberty, particularly in children with PHIV with baseline vitamin D deficiency or insufficiency, are needed.
It is unclear why we found no associations with LS-BMD/BMC in either group or with TB-BMC in PHEU children. In contrast to these studies, we evaluated the effect of categorically low 25(OH)D compared with 25(OH)D as a continuous variable. This is based on clinical evidence that the relationship between 25(OH)D and BMD may not be linear and that those at the lowest levels of 25(OH)D may benefit most from supplementation.21 The lack of association between high PTH and bone outcomes in our study is possibly a result of competing reasons for higher PTH values, including low 25(OH)D, additional requirements for calcium and phosphate during rapid bone accrual, and effects of TDF on PTH.12 This is supported by our finding of lower TB-BMD when high PTH was accompanied by low 25(OH)D.
Vitamin D deficiency is common in the United States.36–38 The 40% prevalence of low 25(OH)D in our cohort was similar to those of cohorts of healthy children in the northeastern United States37 and PHIV children in New York City.7 Our prevalence of vitamin D deficiency was higher than the 24% observed in 6- to 18-year-old children in the National Health and Nutrition Examination Survey representative US sample of this age group,38 but lower than the ≥50% reported in behaviorally HIV-infected adolescents.12,13 Differences across studies are likely attributable to age, race, prevalence of obesity, latitude, sun exposure, season of sampling, and dietary intake.
While low 25(OH)D was equally prevalent in our PHIV and PHEU children overall after adjustment for known confounders,37,39 low 25(OH)D concentrations may be more common in PHIV receiving EFV than in PHEU children, although our power to detect a significant difference between groups may be too low. This is consistent with adult studies14 and may be explained by in vitro evidence of EFV induction of the P450 enzyme CYP24,40 which converts 25(OH)D to its inactive form, calcitroic acid. PHIV children had higher vitamin D intake than did PHEU, but HIV providers may check 25(OH)D levels in their PHIV patients and recommend supplementation.
Calcium is important to optimize bones and tooth mineralization and for catalytic and mechanical functions throughout the body. The body tightly regulates ionized calcium levels. When the calcium supply is insufficient, PTH concentrations increase. PTH increases serum calcium through a variety of mechanisms. PTH mobilizes calcium adsorbed to the bone surface by breaking down bone mineral and matrix, and it stimulates conversion of 25(OH)D to 1,25-dihydroxyvitamin D (1,25(OH)(2)D), which increases gut calcium absorption and renal calcium reabsorption. During the rapid linear growth and bone accrual of puberty, there is an increased demand for calcium and phosphate, and PTH levels increase.41,42 PTH measurements also provide an assessment of the level of “stress” on the system as a result of low 25(OH)D concentrations, although the degree of serum PTH suppression may not determine optimal vitamin D status in children.43
TDF use has been previously associated with increases in serum concentrations of PTH,12,44 with multiple mechanisms implicated. TDF appears to have effects on both bone and hormones, such as fibroblast growth factor-23 and 1,25(OH)2D, that may indirectly increase PTH.45–47 TDF use can also result in renal tubular dysfunction stimulating the production of PTH and in renal phosphate wasting,44 which may, in part, be PTH mediated.12 In HIV-infected adolescents, baseline PTH levels were higher in TDF users regardless of 25(OH)D status. With vitamin D supplementation, PTH levels decreased in the TDF group but did not change in those not receiving TDF.12 In our cohort, PTH levels were higher in those with low 25(OH)D, highest at Tanner stages 3–4, the time of most rapid bone accrual, and higher among TDF users. PTH concentrations were not strongly associated with serum calcium among TDF users, suggesting other mechanisms for elevated PTH.
Our study has several limitations. Although 25(OH)D is a stable vitamin D metabolite with a biological half-life of 2–3 weeks, levels vary by season; thus, one measurement may not represent the average yearly level.48 However, children with 25(OH)D deficiency at one time of the year tend to be deficient at other times during the year,49 which favors using the ≤20 ng/mL cutoff recommended by the Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.21 Although imperfect, we adjusted for season when evaluating the prevalence or differences in 25(OH)D by subgroups. We recognize that the 20 ng/mL cutoff is based upon what is needed to prevent rickets and osteomalacia,21 but concentrations required for optimal bone and immunological health are likely higher.50 Using this lower threshold, we could examine characteristics of those most likely to have clinically significant deficiency. Because this was a cross-sectional study where 25(OH)D, PTH, and DXA parameters were measured within 1 year of each other, we could not establish a temporal relationship between low 25(OH)D or high PTH and subsequent bone accrual. Although this is an important limitation, BMD ranking tracks well over time in healthy children such that those who ranked among the lowest earlier in childhood also ranked among the lowest later in adolescence and those who ranked highest generally remained high.51 When evaluating prevalence of high PTH, confidence intervals were wide because of a few children having high PTH. Finally, our findings might not be generalizable to populations other than those in the United States where there is a difference in the distribution of continental ancestry and nutritional status.
Children gain more than half of their peak bone mass during adolescence with the greatest increase following the pubertal growth spurt, highlighting the need to identify modifiable factors during this critical period that could improve bone accrual. This study afforded a unique opportunity to further quantify the risk factors for poor bone health, specifically low 25(OH)D. This may lead to novel vitamin D supplementation trials that could ameliorate deficits and improve bone health at critical developmental stages.
The authors thank the children and families for their participation in PHACS and the individuals and institutions involved in the conduct of PHACS. (Principal Investigator: George Seage; Project Director: Julie Alperen) and the Tulane University School of Medicine (HD052104) (Principal Investigator: R.B.V.; Co-Principal Investigators: Kenneth Rich, Ellen Chadwick; Project Director: Patrick Davis). Data management services were provided by Frontier Science and Technology Research Foundation (PI: Suzanne Siminski), and regulatory services and logistical support were provided by Westat, Inc (PI: Julie Davidson). ssThe following institutions, clinical site investigators, and staff participated in conducting PHACS AMP and AMP Up in 2015, in alphabetical order: Ann & Robert H. Lurie Children's Hospital of Chicago: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter; Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynnette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Mahboobullah Baig, Anna Cintron; Children's Diagnostic & Treatment Center: Ana Puga, Sandra Navarro, Patricia A. Garvie, James Blood; Children's Hospital, Boston: Sandra K. Burchett, Nancy Karthas, Betsy Kammerer; Jacobi Medical Center: Andrew Wiznia, Marlene Burey, Molly Nozyce; Rutgers—New Jersey Medical School: Arry Dieudonne, Linda Bettica; St. Christopher's Hospital for Children: J.S.C., Maria Garcia Bulkley, Latreaca Ivey, Mitzie Grant; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Heida Rios, Vivian Olivera; Tulane University School of Medicine: M.S., Medea Gabriel, Patricia Sirois; University of California, San Diego: S.A.S., Kim Norris, Sharon Nichols; University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Juliana Darrow, Emily Barr, Paul Harding; University of Miami: Gwendolyn Scott, Grace Alvarez, Anai Cuadra.
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25-hydroxy-vitamin D; parathyroid hormone; HIV infection; children; bone mineral density
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