Abstract
In 5,187 persons from the Cardiovascular Health Study, there was no significant association of dietary intakes of aromatic amino acids (AAA) with areal BMD of the hip or body composition. However, those who had the lowest dietary intakes of AAA were at increased risk for incident hip fractures.
Purpose:
Prior studies of the association of protein intake with osteoporosis are conflicting, and have not directly examined the relationship of aromatic amino acids (AAA) with fractures, areal bone mineral density (aBMD) and body composition. We sought to determine the relationship of dietary intakes of AAA with osteoporosis parameters in elderly men and women.
Methods:
5,187 men and women aged ≥ 65 years from the Cardiovascular Health Study (CHS) with dietary intakes of AAA (tryptophan, phenylalanine, tyrosine) estimated by food frequency questionnaire (FFQ) were included. We examined the relationship between a one-time estimate of daily dietary AAA intake with risk of incident hip fractures over a median of 13.2 years of fracture follow-up. A subset (n=1,336) who had dual energy X-ray absorptiometry (DXA) performed were included in a cross-sectional analysis of the association of dietary AAA intake with aBMD of the total hip and measurements of body composition.
Results:
In multivariable models adjusted for demographic and clinical variables, medication use and diet, higher dietary AAA intake was not significantly associated with incident hip fractures. All hazard ratios (HR) were less than one (tryptophan, HR 0.14, 95% CI 0.01 to 1.89; phenylalanine, HR 0.60, 95% CI 0.23 to 1.55; tyrosine, HR 0.59, 95% CI 0.27 to 1.32), but confidence intervals were wide and included no difference. However, in post hoc analyses, the lowest quartile of intake for each AAA was associated with an increased risk for hip fracture compared to higher quartiles (p≤0.047 for all). Dietary AAA intakes were not significantly associated with total hip aBMD or any measurements of body composition.
Conclusion:
Overall, there was no significant association of dietary AAA intake with hip fractures, aBMD of the hip or body composition. However, there may be a subset of elderly individuals with low dietary intakes of AAA who are at increased for hip fractures.
Keywords: fractures, body composition, nutrition, aging
Introduction
Optimal nutrition is important for skeletal health. Approximately 40–80% of patients hospitalized for a hip fracture are malnourished (1). The prevalence of dietary protein insufficiency increases in individuals over 70 years of age (2). Higher protein intake might be beneficial to the skeleton by increasing insulin‐like growth factor 1 (IGF‐1) (3). However, dietary protein also increases metabolic acidosis, which may increase urinary calcium excretion, adversely affecting bone (4). Beneficial associations of higher protein intakes on bone mineral density (BMD), fractures and bone microarchitecture have been reported in some (5–8) but not all, studies (9, 10). Results from randomized controlled trials of the effects of either increased dietary intakes of protein or protein supplements on lumbar spine (LS) aBMD have also been inconsistent, with some (11–13) reporting that the lower-protein groups lost significantly more or gained significantly less LS aBMD than the higher-protein groups after one year, whereas others (14–17), showed no significant difference in LS aBMD. The relative impact of specific amino acids on osteoporosis is just starting to gain attention. Dietary intakes of six nonessential amino acids (alanine, arginine, glutamic acid, leucine, lysine and proline) were positively associated with lumbar spine (LS) aBMD in discordant identical women twin-pairs (18). In a metabolomics study of aBMD including Caucasian women, serum concentrations of five serum amino acids (GABA, threonine, cysteine, taurine and glutamic acid) were significantly positively associated with BMD of the hip (19). Glutamine levels (20) have also been reported to be positively associated with LS aBMD in postmenopausal women of Asian descent.
Aromatic amino acids (AAA) are characterized by a benzene ring in the side group and include tryptophan, phenylalanine and tyrosine. Humans can convert phenylalanine to tyrosine via hydroxylation in the liver and kidneys; however, tryptophan and phenylalanine must be acquired through dietary means and are thus considered “essential” amino acids. In the aging mouse model, AAAs increase bone formation and down-regulate the gene expression of factors necessary for early and late differentiation of osteoclasts, resulting in a net anabolic effect on bone (21, 22). In rats, tryptophan-free diets significantly reduce serum concentrations of osteocalcin and IGF-1 with subsequent shifts towards bone resorption (23). Physiologically, tryptophan binds the extracellular calcium-sensing receptor and activates anabolic signaling pathways in bone marrow mesenchymal stem cells (24, 25). However, oxidation of tryptophan and tyrosine via reactive oxidation species impairs their abilities to promote bone formation and may contribute to bone loss (26).
The main sources of aromatic amino acids are dietary proteins from fish, beef, pork and chicken although vegetable protein like soy is also rich in aromatic AAs (27). Other sources of aromatic amino acids include nuts and eggs. Tyrosine is the precursor for a number of bioactive molecules such as dopamine, epinephrine and norepinephrine; it is also a precursor for the synthesis of thyroid hormone (28). In patients with phenylketonuria, where dietary phenylalanine is restricted and tyrosine levels are low, baseline bone density is significantly lower than what is seen in controls (29). Tryptophan is also the precursor for a number of bioactive molecules including serotonin, melatonin and niacin, both of which can impact bone mass (30, 31).
To our knowledge, there are no previous reports on the association between dietary intakes of AAA in humans and osteoporotic fractures, aBMD or body composition. The objectives of this study were to examine the impact of dietary intakes of tryptophan, phenylalanine, and tyrosine on incident hip fractures, aBMD and body composition in older community-dwelling African American and Caucasian men and women.
Methods
Participants
The Cardiovascular Health Study (CHS) is a longitudinal study of elderly community-dwelling men and women (age ≥ 65 years) designed to monitor risk factors for the development and progression of cardiovascular disease and stroke (32). Random samples of Medicare-eligible individuals were recruited from four participating clinic sites across the United States: (1) Forsyth County, North Carolina; (2) Sacramento County, California; (3) Washington County, Maryland; and (4) Allegheny County, Pennsylvania. Participants were excluded if they were institutionalized, unable to consent without a representative, planning to move away from the clinic site within 3 years of recruitment, wheelchair-dependent, on hospice care, or treated with chemotherapy or radiation for cancer.
There were 5,888 participants in the CHS cohort. Participants had yearly in-person exams performed from 1989 to 1999 and again from 2005 to 2006. Telephone interviews were conducted annually at the midpoint between annual in-person exams from 1989 to 1999 and every 2 years thereafter. Clinic sites in California and Pennsylvania performed dual energy X-ray absorptiometry (DXA) on 1,591 participants between 1994 and 1995.
Participants with available dietary data (n=5,201) were excluded from analyses if they had reported extremes in total energy intake (≤ 500 kcal/day or ≥ 5,000 kcal/day) (n=14). All remaining participants (n=5,187) were included in the incident hip fracture analyses. Those with dietary data and aBMD measurements were included in the aBMD of the hip and body composition analyses (n=1,336). The study was approved by the Institutional Review Board (IRB) at each site. All participants gave written informed consent.
Predictors
The primary predictors were daily dietary intakes of tryptophan, phenylalanine and tyrosine from 1989 to 1990 (the year following baseline assessments) in CHS. Dietary intake was quantified using a qualitative, picture-sort food frequency questionnaire (FFQ). In this FFQ, the participant was given a deck consisting of 99 cards with a food or food group. Participants then sorted each card into 1 of 5 categories based on frequency of consumption: (1) almost every day, (2) 1–4 times per week, (3) 1–3 times per month, (4) 5–10 times per year and (5) never. In a sub study validation of the CHS FFQ including 47 female and 49 males aged 66 to 100 from the CHS, estimates of mean nutrient intakes from the picture-sort FFQ used in CHS were comparable to estimates based on 24-hour recalls, and correlations with reference data were similar to those reported in the literature for conventionally administered FFQs (33).
Outcomes
Incident hip fractures
An incident hip fracture was identified using International Classification of Disease 9th Revision (ICD-9) code 820.xx to query hospital discharge diagnoses. During the study period, CHS collected hospitalization data, including discharge summaries, from participants every 6 months and cross-referenced them to Medicare claims data to confirm their accuracy and to identify any hospitalizations not self-reported. Hip fractures from motor vehicle accidents or other severe injuries were excluded (E810.xx-825.xx). Follow-up for incident hip fracture began in 1989–1990 (following FFQ collection) and was continued to a hip fracture event, death, loss to follow-up, or June 30, 2013, whichever occurred first.
Areal BMD and body composition measurements
DXA scans were performed with Hologic QDR-2000 densitometers (Hologic, Inc., Waltham, MA) using array beam mode from 1995–1996. All images were interpreted at the University of California in San Francisco’s reading center using Hologic Software, version 7.10. Standardized positioning and use of QDR software was based on the manufacturer’s recommended protocol. Areal BMD of the total hip was used in these analyses. The coefficient of variation for the total hip aBMD was 0.75% (35). Body composition measurements, including total body aBMD (g/cm2), percent fat (%), total fat (kg), percent lean (%), and total lean (kg), were also obtained (36).
Covariates
Covariates were assessed at the same time as the diet assessment (from 1989 to 1990). Age, sex and race were self-reported. Weight was measured using a calibrated balance beam scale. Height was measured using a wall-mounted stadiometer. Weight (kg) and height (cm) were used to calculate body mass index (BMI) (kg/m2). Renal function was assessed with cystatin C. A history of diabetes was defined as use of insulin or oral hypoglycemic medication, non-fasting glucose ≥ 200 mg/dL, or fasting glucose ≥ 126 mg/dL. Impaired fasting glucose was defined as fasting glucose of 100–125 mg/dL (37). Highest level of education achieved was defined as ≥12th grade or <12th grade, and levels of physical activity (total kcal/week) were self-reported. Daily dietary intake of calcium, vitamin D, energy, and protein were estimated from the FFQ.
Medication use data were obtained through review of prescription bottle labels. Medications included in the analysis were estrogens, estrogen/progesterone combinations, loop diuretics, thiazide diuretics, thyroid medications, anti-depressants, anti-psychotics, benzodiazepines, oral corticosteroids, and bisphosphonates. Smoking history (current, former, and never) and current alcohol use (0, 1–7, or >7 drinks/week) were self-reported. Frailty status was included: frail was defined as 3 or more of unintentional weight loss of ≥10 pounds in past year, self-reported exhaustion, weak grip strength (calculated as the mean of three serial measurements of the dominant hand adjusted for gender and BMI), low walking speed (timed walk over 4.57 m or 15 feet at usual pace by height and sex) and low physical activity. Intermediate (prefrail) was defined as 1 or 2 of the above criteria; or not frail as none of these paramters present (38) (39).
C-reactive protein (CRP) was measured as a marker of inflammation. CRP was measured with an enzyme-linked immunosorbent assay developed at the CHS central blood laboratory. The interassay coefficient of variation was 5.5% (40, 41).
Statistical analysis
We described the cohort and compared baseline participant characteristics across tryptophan, phenylalanine and tyrosine using linear trend tests for continuous variables and chi-square tests for categorical variables. For incident hip fracture, we used Cox regression to estimate hazard ratios (HR). We used nested models: M0 unadjusted; M1 adjusting for age, race, and clinic site; M2 further adjusting for BMI, cystatin C, diabetes, education, dietary calcium and vitamin D intakes, medication use, physical activity, smoking, alcohol, and frailty status; and M3 (final multivariable adjusted models) further adjusting for total energy intake and dietary protein intake. Linear regression analysis was used to estimate the associations of the three dietary predictors with aBMD of the total hip and body composition measures. In additional to adjusting all models for sex, we stratified analyses separately for men and women due to potentially different pathways for the association of AAA intakes with outcomes. We determined the interaction of CRP with the association of each AAA with incident hip fracture, aBMD of the total hip and measurements of body composition
We used all predictors on a continuous scale. To address the functional form of the predictors in the models, we used generalized additive models (GAMs) with splines. We found no statistically significant departures from linearity in linear regression for aBMD and the body composition measures, or in Cox regression for incident hip fracture. However, we observed some slight curvature in the low values of predictors in the incident hip fracture analysis. Thus, as a post hoc analysis, we contrasted the lowest quartile with combined quartiles two to four. We did not adjust for multiple testing.
Analyses were conducted using R (R Development Core Team) environment for statistical computing (42).
Results
725 of 5,187 persons (14.0%) included in these analyses sustained a hip fracture in CHS during follow-up. The overall incidence rate for hip fractures was 1.08 per 100 person-years (95% CI 0.91 to 1.3). There were 535 hip fractures in 2,956 women for an incidence rate of 1.30 per 100 person-years of follow-up (95% CI 1.14 to 1.48) and 190 hip fractures in 2,231 men for an incidence rate of 0.73 per 100 person-years of follow-up (95% CI 0.44 to 1.21). The mean energy intake was 2,030 ± 681 kcal/day. Baseline characteristics of the study population in the lowest and highest quartiles of intake for each aromatic amino acid are shown in Table 1. Complete data including all quartiles for each aromatic amino acid is presented in supplemental Tables 1a–c in the appendix.
Table 1.
Baseline Characteristics by Type of Aromatic Amino Acid Intake
| Tryptophan | Phenylalanine | Tyrosine | ||||
|---|---|---|---|---|---|---|
| Characteristic | Quartile 1 n=1310 |
Quartile 4 n=1273 |
Quartile 1 n=1299 |
Quartile 4 n=1294 |
Quartile 1 n=1308 |
Quartile 4 n=1296 |
| Age (years) (mean ±SD) | 72.9 ±5.7 | 73.0 ±5.8 | 72.9 ±5.6 | 73.0 ±5.8 | 72.9 ±5.7 | 73.0 ±5.7 |
| BMI (kg/m2) (mean ±SD)* | 26.2±4.6 | 26.7±4.6 | 26.2 ±4.5 | 26.7±4.7 | 26.2 ±4.5 | 26.7±4.7 |
| Male sex (%) | 500 (38.2%) | 596 (46.8%) | 495 (38.1%) | 615 (47.5%) | 498 (38.1%) | 609 (47%) |
| Black race (%) | 54 (4.1%) | 75 (5.9%) | 53 (4.1%) | 80 (6.2%) | 55 (4.2%) | 77 (5.9%) |
| Cystatin C (mean ±SD)* | 1.05 ±0.34 | 1.07 ±0.3 | 1.05 ±0.34 | 1.07 ±0.3 | 1.05 ±0.34 | 1.07 ±0.3 |
| Diabetes status (%)* | ||||||
| Not diabetic | 937 (72.3%) | 874 (68.9%) | 933 (72.6%) | 891 (69.1%) | 942 (72.9%) | 883 (68.4%) |
| Impaired fasting glucose | 171 (13.2%) | 188 (14.8%) | 175 (13.6%) | 188 (14.6%) | 171 (13.2%) | 194 (15%) |
| Diabetes | 188 (14.5%) | 206 (16.2%) | 178 (13.8%) | 210 (16.3%) | 180 (13.9%) | 213 (16.5%) |
| Education (≥12 grade) (%)* | 527 (40.3%) | 559 (44.1%) | 526 (40.6%) | 560 (43.4%) | 532 (40.8%) | 570 (44.2%) |
| Calcium intake (mg/day) (mean ±SD) | 752 ±218 | 1349 ±330 | 751 ±220 | 1345 ±330 | 749 ±220 | 1344 ±330 |
| Vitamin D intake (IU/day) (mean ±SD) | 195 ±121 | 528 ±227 | 204 ±130 | 519 ±230 | 202 ±129 | 517 ±230 |
| Physical activity levels (kcal/week) (median (IQR))* | 600 (102–1592) | 735 (189–1625) | 630 (120–1641) | 735 (180–1620) | 630 (128–1620) | 735 (174–1620) |
| Clinic site (%) | ||||||
| Bowman Gray NC | 455 (34.7%) | 200 (15.7%) | 442 (34%) | 203 (15.7%) | 454 (34.7%) | 200 (15.4%) |
| Davis CA | 359 (27.4%) | 297 (23.3%) | 358 (27.6%) | 286 (22.1%) | 363 (27.8%) | 292 (22.5%) |
| Hagerstown MD | 289 (22.1%) | 402 (31.6%) | 292 (22.5%) | 409 (31.6%) | 294 (22.5%) | 405 (31.2%) |
| Pittsburgh PA | 207 (15.8%) | 374 (29.4%) | 207 (15.9%) | 396 (30.6%) | 197 (15.1%) | 399 (30.8%) |
| Medication use (%) | ||||||
| Loop diuretic | 37 (2.8%) | 33 (2.6%) | 39 (3%) | 39 (3%) | 37 (2.8%) | 37 (2.9%) |
| Thiazide diuretics | 194 (14.8%) | 181 (14.2%) | 194 (14.9%) | 178 (13.8%) | 191 (14.6%) | 178 (13.7%) |
| Thyroid medications* | 122 (9.3%) | 88 (6.9%) | 115 (8.9%) | 88 (6.8%) | 114 (8.7%) | 85 (6.6%) |
| Estrogen and estrogen/progesterone combinations | 19 (1.5%) | 19 (1.5%) | 19 (1.5%) | 18 (1.4%) | 20 (1.5%) | 18 (1.4%) |
| Antidepressants | 27 (2.1%) | 19 (1.5%) | 28 (2.2%) | 19 (1.5%) | 26 (2%) | 21 (1.6%) |
| Antipsychotics | 146 (11.1%) | 131 (10.3%) | 146 (11.2%) | 128 (9.9%) | 146 (11.2%) | 129 (10%) |
| Benzodiazepines | 135 (10.3%) | 126 (9.9%) | 133 (10.2%) | 123 (9.5%) | 133 (10.2%) | 124 (9.6%) |
| Corticosteroids* | 24 (1.8%) | 20 (1.6%) | 25 (1.9%) | 24 (1.9%) | 27 (2.1%) | 23 (1.8%) |
| Bisphosphonates | 28 (2.1%) | 30 (2.4%) | 28 (2.2%) | 28 (2.2%) | 29 (2.2%) | 28 (2.2%) |
| Smoking status (%)* | ||||||
| Current | 164 (12.5%) | 151 (11.9%) | 157 (12.1%) | 161 (12.4%) | 156 (11.9%) | 161 (12.4%) |
| Former | 533 (40.7%) | 540 (42.4%) | 532 (41%) | 547 (42.3%) | 537 (41.1%) | 551 (42.5%) |
| Never | 613 (46.8%) | 582 (45.7%) | 610 (47%) | 586 (45.3%) | 615 (47%) | 584 (45.1%) |
| Alcohol use (drinks/week) (%)* | ||||||
| 0 | 684 (52.3%) | 608 (47.8%) | 168 (12.9%) | 165 (12.8%) | 163 (12.5%) | 161 (12.4%) |
| 1–7 | 462 (35.3%) | 505 (39.7%) | 664 (51.2%) | 626 (48.4%) | 683 (52.3%) | 620 (47.9%) |
| >7 | 163 (12.5%) | 159 (12.5%) | 466 (35.9%) | 502 (38.8%) | 461 (35.3%) | 514 (39.7%) |
| Frailty status (%)* | ||||||
| Not frail | 557 (46.9%) | 512 (45%) | 562 (47.7%) | 518 (44.7%) | 568 (47.9%) | 516 (44.3%) |
| Prefrail | 547 (46.1%) | 544 (47.8%) | 535 (45.4%) | 556 (47.9%) | 537 (45.3%) | 559 (48%) |
| Frail | 83 (7%) | 83 (7.3%) | 81 (6.9%) | 86 (7.4%) | 81 (6.8%) | 89 (7.6%) |
| Protein intake (g/day) (mean ±SD) | 56.23 ±10.83 |
148.49 ±27.11 | 56.04 ±10.7 |
148.07 ±27.08 |
56.25 ±10.88 |
147.96 ±27.16 |
| Energy intake (kilocalories) (mean ±SD) | 1369.00 ±302.32 | 2869.78 ±558.95 | 1354.67 ±287.93 | 2877.18 ±547.99 | 1368.47 ±300.92 | 2868.6 ±555.39 |
Data were missing for the following variables: Cystatin C (n=673), frailty status (n=488), Diabetes status (n=33), Alcohol use (n=51), BMI (n=16), Education (≥12 grade) (n=14), Physical activity levels (n=5), Thyroid medications (n=4), Corticosteroids n= 4, Smoking status (n=3).
The mean intakes of tryptophan, phenylalanine and tyrosine were 1.13± 0.439 g/day, 4.25± 1.573 g/day and 3.46 ± 1.285 g/day, respectively. Penalized splines with 4 degrees of freedom of these AAA intakes in model M3 are shown in Figures 1a, b, c. Quartiles of each AAA intake were as follows: tryptophan: Quartile 1: 0.18–0.82 g/day; Quartile 2: 0.82–1.08 g/day; Quartile 3: 1.08–1.39 g/day; and Quartile 4: 1.39–3.73 g/day; phenylalanine: Quartile 1: 0.75–3.14 g/day; Quartile 2: 3.14–4.05 g/day; Quartile 3: 4.05–5.16 g/day; and Quartile 4: 5.16–13.2 g/day; and tyrosine: Quartile 1: 0.57–2.55 g/day; Quartile 2: 2.56–3.29 g/day; Quartile 3: 3.29–4.20 g/day; and Quartile 4: 4.21–10.93 g/day. The mean intakes of each AAA was significantly higher in men compared to women (p<0.01) but were not significantly associated with age. Tryptophan, phenylalanine and tyrosine intakes were not significantly associated with incident hip fractures in fully adjusted models (M3) overall or by sex (Table 2), although all HR in fully adjusted (M3) models were below 1.
Figure 1a.
Penalized splines with 4 degrees of freedom of tryptophan intake in model M3
Figure 1b.
Penalized splines with 4 degrees of freedom of phenylalanine intake in model M3
Figure 1c.
Penalized splines with 4 degrees of freedom of tyrosine intake in model M3
Table 2.
Incident Hip Fractures by Aromatic Amino Acid Intake
| All | Women | Men | ||
|---|---|---|---|---|
| HR (95% CI) | HR (95% CI) | HR (95% CI) | ||
| Tryptophan | MV0 | 0.98 (0.82, 1.16) | 0.98 (0.80, 1.20) | 1.08 (0.77, 1.51) |
| MV1 | 1.04 (0.88, 1.24) | 0.99 (0.80, 1.22) | 1.10 (0.78, 1.55) | |
| MV2 | 0.86 (0.64,1.16) | 0.74 (0.52,1.05) | 0.17 (0.63, 2.20) | |
| MV3 | 0.14 (0.01, 1.89) | 0.27 (0.01,5.75) | 0.10 (0,38.14) | |
| Phenylalanine | MV0 | 0.99 (0.95, 1.04) | 1.00 (0.94, 1.06) | 1.02 (0.93, 1.12) |
| MV1 | 1.01 (0.96, 1.06) | 1.00 (0.94, 1.06) | 1.03 (0.93, 1.13) | |
| MV2 | 0.96 (0.89, 1.05) | 0.92 (0.84, 1.02) | 1.04 (0.87, 1.23) | |
| MV3 | 0.60 (0.23, 1.55) | 0.82 (0.26, 2.56) | 0.17 (0.02, 1.36) | |
| Tyrosine | MV0 | 0.99 (0.93, 1.05) | 0.99 (0.92, 1.06) | 1.03 (0.91, 1.15) |
| MV1 | 1.01 (0.95, 1.07) | 0.99 (0.92, 1.06) | 1.03 (0.92, 1.16) | |
| MV2 | 0.95 (0.86, 1.05) | 0.90 (0.80, 1.01) | 1.05 (0.85, 1.29) | |
| MV3 | 0.59 (0.27, 1.32) | 0.53 (0.20, 1.37) | 0.32 (0.06, 1.74) | |
MV0: unadjusted
Sample Size/Number of Events: 5187/725 (Women 2956/524); (Men 2231/190)
MV1: age, sex, race, clinic site
Sample Size/Number of Events: 5187/725 (Women 2956/524); (Men 2231/190)
MV2: age, sex, race, clinic site, BMI, cystatin C, physical activity, diabetes, education, calcium and vitamin D intake, medication use, smoking, alcohol and frailty
Sample Size/Number of Events:4040/573 (Women 2327/414); (Men 1568/127)
MV3: age, sex, race, clinic site, BMI, cystatin C, physical activity diabetes, education, calcium and vitamin D intake, medication use, smoking, alcohol, frailty, protein and total energy (caloric) intake
Sample Size/Number of Events: 4040/573 (Women 2327/414); (Men 1568/127)
Tryptophan, phenylalanine and tyrosine intakes were not significantly associated with any measures of aBMD or body composition after final multivariable adjustment (M3) (Tables 3, 4, 5).
Table 3.
Bone Mineral Density and Body Composition Measurements by Tryptophan Intake
| All | Women | Men | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| β | SE | 95%CI | β | SE | 95%CI | β | SE | 95%CI | ||
| Total Hip aBMD (g/cm2 ) | MV0 | 0.99 | 1.15 | (−1.26,3.24) | −2.00 | 1.17 | (−4.29,0.29) | 1.58 | 1.59 | (−1.53,4.68) |
| MV1 | −0.73 | 0.92 | (−2.53,1.07) | −2.47 | 1.12 | (−4.67,−0.27) | 1.50 | 1.53 | (−1.51,4.51) | |
| MV2 | −1.18 | 1.32 | (−3.77,1.42) | −1.91 | 1.54 | (−4.93,1.12) | 0.31 | 2.48 | (−4.55,5.16) | |
| MV3 | 2.27 | 12.14 | (−21.53,26.08) | −0.22 | 13.81 | (−27.28,26.85) | 16.39 | 23.67 | (−30.01,62.79) | |
|
Total body aBMD (g/cm2 ) |
MV0 | 1.35 | 1.00 | (−0.60,3.31) | −0.80 | 0.95 | (−2.67,1.07) | 0.90 | 1.21 | (−1.46,3.26) |
| MV1 | −0.47 | 0.74 | (−1.92,0.97) | −1.28 | 0.93 | (−3.11,0.54) | 0.54 | 1.20 | (−1.8,2.88) | |
| MV2 | −2.07 | 1.13 | (−4.29,0.15) | −2.74 | 1.36 | (−5.40,−0.09) | −1.31 | 2.05 | (−5.33,2.72) | |
| MV3 | 0.58 | 10.45 | (−19.91,21.07) | 4.14 | 12.19 | (−19.76,28.04) | −1.73 | 19.64 | (−40.23,36.77) | |
|
Percent Fat (%) |
MV0 | −2.01 | 0.64 | (−3.26,−0.75) | −0.61 | 0.67 | (−1.93,0.71) | −1.68 | 0.66 | (−2.98,−0.38) |
| MV1 | −0.98 | 0.48 | (−1.91,−0.04) | −0.75 | 0.67 | (−2.06,0.55) | −1.24 | 0.66 | (−2.54,0.06) | |
| MV2 | −0.68 | 0.58 | (−1.82,0.45) | 0.11 | 0.74 | (−1.35,1.57) | −2.28 | 0.91 | (−4.07,−0.49) | |
| MV3 | −8.80 | 5.32 | (−19.23,1.64) | −4.80 | 6.68 | (−17.9,8.31) | −13.28 | 8.74 | (−30.41,3.86) | |
| Total Fat (kg) | MV0 | −1.68 | 0.62 | (−2.89,−0.48) | −0.85 | 0.85 | (−2.52,0.82) | −1.89 | 0.79 | (−3.45,−0.33) |
| MV1 | −1.31 | 0.58 | (−2.45,−0.16) | −1.18 | 0.83 | (−2.81,0.46) | −1.44 | 0.78 | (−2.98,0.09) | |
| MV2 | −1.24 | 0.56 | (−2.34,−0.14) | −0.37 | 0.70 | (−1.74,1.01) | −2.84 | 0.93 | (−4.67,−1.01) | |
| MV3 | −6.91 | 5.15 | (−17.01,3.19) | −2.24 | 6.30 | (−14.58,10.1) | −13.74 | 8.93 | (−31.24,3.75) | |
| Percent Lean (%) | MV0 | 2.01 | 0.64 | (0.75,3.26) | 0.61 | 0.67 | (−0.71,1.93) | 1.68 | 0.66 | (0.38,2.98) |
| MV1 | 0.98 | 0.48 | (0.04,1.91) | 0.75 | 0.67 | (−0.55,2.06) | 1.24 | 0.66 | (−0.06,2.54) | |
| MV2 | 0.68 | 0.58 | (−0.45,1.82) | −0.11 | 0.74 | (−1.57,1.35) | 2.28 | 0.91 | (0.49,4.07) | |
| MV3 | 8.80 | 5.32 | (−1.64,19.23) | 4.80 | 6.68 | (−8.31,17.9) | 13.28 | 8.74 | (−3.86,30.41) | |
| Total Lean (kg) | MV0 | 1.33 | 0.67 | (0.02,2.65) | 0.01 | 0.44 | (−0.85,0.87) | 0.32 | 0.67 | (−0.99,1.62) |
| MV1 | −0.05 | 0.37 | (−0.78,0.68) | −0.25 | 0.44 | (−1.10,0.60) | 0.23 | 0.64 | (−1.02,1.48) | |
| MV2 | −0.32 | 0.54 | (−1.37,0.74) | −0.07 | 0.57 | (−1.19,1.05) | −0.80 | 1.08 | (−2.93,1.32) | |
| MV3 | 2.36 | 4.95 | (−7.34,12.06) | 2.77 | 5.14 | (−7.29,12.84) | 0.10 | 10.37 | (−20.23,20.42) | |
| Total Body Mass (kg) | MV0 | −0.35 | 0.92 | (−2.14,1.45) | −0.84 | 1.15 | (−3.09,1.41) | −1.57 | 1.22 | (−3.95,0.81) |
| MV1 | −1.35 | 0.81 | (−2.94,0.24) | −1.43 | 1.12 | (−3.62,0.77) | −1.21 | 1.17 | (−3.50,1.08) | |
| MV2 | −1.56 | 0.82 | (−3.16,0.05) | −0.44 | 1.00 | (−2.39,1.52) | −3.64 | 1.46 | (−6.51,−0.77) | |
| MV3 | −4.55 | 7.56 | (−19.38,10.27) | 0.53 | 8.96 | (−17.03,18.1) | −13.65 | 14.01 | (−41.11,13.82) | |
MV0: unadjusted
Sample Size: 1336 (Women 767; Men 569)
MV1: age, race, clinic site, sex
Sample Size:1336 (Women 767; Men 569)
MV2: age, sex, race, clinic site, BMI, cystatin C, physical activity, diabetes, education, calcium and vitamin D intake, medication use, smoking, alcohol and frailty
Sample Size :1185 (Women 697; Men 488)
MV3: age, sex, race, clinic site, BMI, cystatin C, physical activity, diabetes, education, calcium and vitamin D intake, medication use, smoking, alcohol, frailty, protein and total energy (caloric) intake
Sample Size:1185 (Women 697; Men 488)
Sample size for total hip (sample size for other measurements of body composition were similar)
Table 4.
Body Mineral Density and Body Composition Measurements by Phenylalanine Intake
| All | Women | Men | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| β | SE | 95%CI | β | SE | 95%CI | β | SE | 95%CI | ||
|
Total Hip aBMD (g/cm2 ) |
MV0 | 0.36 | 0.32 | (−0.27,0.99) | −0.53 | 0.33 | (−1.17,0.12) | 0.42 | 0.44 | (−0.45,1.29) |
| MV1 | −0.17 | 0.26 | (−0.67,0.34) | −0.62 | 0.32 | (−1.24,−0.001) | 0.40 | 0.43 | (−0.44,1.25) | |
| MV2 | −0.28 | 0.37 | (−0.99,0.44) | −0.48 | 0.43 | (−1.32,0.36) | 0.12 | 0.68 | (−1.21,1.45) | |
| MV3 | 7.80 | 4.41 | (−0.85,16.45) | 4.25 | 5.25 | (−6.03,14.54) | 15.20 | 8.00 | (−0.48,30.88) | |
|
Total body aBMD (g/cm2 ) |
MV0 | 0.46 | 0.28 | (−0.09,1.00) | −0.23 | 0.27 | (−0.76,0.29) | 0.27 | 0.34 | (−0.39,0.93) |
| MV1 | −0.12 | 0.21 | (−0.53,0.29) | −0.35 | 0.26 | (−0.86,0.17) | 0.17 | 0.34 | (−0.49,0.82) | |
| MV2 | −0.56 | 0.32 | (−1.17,0.06) | −0.78 | 0.38 | (−1.52,−0.04) | −0.29 | 0.56 | (−1.39,0.81) | |
| MV3 | 3.21 | 3.80 | (−4.22,10.66) | −1.47 | 4.64 | (−10.55,7.62) | 10.76 | 6.62 | (−2.21,23.72) | |
|
Percent Fat |
MV0 | −0.58 | 0.18 | (−0.93,−0.23) | −0.15 | 0.19 | (−0.52,0.22) | −0.43 | 0.19 | (−0.80,−0.07) |
| MV1 | −0.23 | 0.13 | (−0.50,0.03) | −0.18 | 0.19 | (−0.54,0.19) | −0.30 | 0.19 | (−0.66,0.07) | |
| MV2 | −0.17 | 0.16 | (−0.49,0.14) | 0.04 | 0.21 | (−0.37,0.44) | −0.59 | 0.25 | (−1.08,−0.10) | |
| MV3 | −1.31 | 1.94 | (−5.11,2.48) | −1.25 | 2.54 | (−6.22,3.73) | −0.34 | 2.96 | (−6.14,5.47) | |
| Total Fat | MV0 | −0.46 | 0.17 | (−0.80,−0.12) | −0.20 | 0.24 | (−0.67,0.26) | −0.49 | 0.22 | (−0.93,−0.06) |
| MV1 | −0.32 | 0.16 | (−0.64,0.01) | −0.28 | 0.24 | (−0.74,0.18) | −0.35 | 0.22 | (−0.78,0.08) | |
| MV2 | −0.32 | 0.16 | (−0.62,−0.02) | −0.09 | 0.20 | (−0.48,0.29) | −0.73 | 0.26 | (−1.23,−0.23) | |
| MV3 | 0.61 | 1.87 | (−3.06,4.28) | 0.49 | 2.39 | (−4.20,5.17) | 2.16 | 3.02 | (−3.77,8.09) | |
| Percent Lean | MV0 | 0.58 | 0.18 | (0.23,0.93) | 0.15 | 0.19 | (−0.22,0.52) | 0.43 | 0.19 | (0.07,0.80) |
| MV1 | 0.23 | 0.13 | (−0.03,0.50) | 0.18 | 0.19 | (−0.19,0.54) | 0.30 | 0.19 | (−0.07,0.66) | |
| MV2 | 0.17 | 0.16 | (−0.14,0.49) | −0.04 | 0.21 | (−0.44,0.37) | 0.59 | 0.25 | (0.10,1.08) | |
| MV3 | 1.31 | 1.94 | (−2.48,5.11) | 1.25 | 2.54 | (−3.73,6.22) | 0.34 | 2.96 | (−5.47,6.14) | |
| Total Lean | MV0 | 0.43 | 0.19 | (0.06,0.80) | 0.01 | 0.12 | (−0.23,0.25) | 0.06 | 0.19 | (−0.30,0.43) |
| MV1 | −0.01 | 0.10 | (−0.22,0.19) | −0.06 | 0.12 | (−0.30,0.18) | 0.05 | 0.18 | (−0.30,0.40) | |
| MV2 | −0.09 | 0.15 | (−0.39,0.20) | −0.02 | 0.16 | (−0.33,0.29) | −0.22 | 0.30 | (−0.80,0.36) | |
| MV3 | 0.45 | 1.80 | (−3.08,3.97) | 1.34 | 1.95 | (−2.49,5.16) | 0.34 | 3.50 | (−6.53,7.21) | |
| Total Mass | MV0 | −0.03 | 0.26 | (−0.53,0.47) | −0.19 | 0.32 | (−0.83,0.44) | −0.43 | 0.34 | (−1.10,0.24) |
| MV1 | −0.33 | 0.23 | (−0.78,0.12) | −0.33 | 0.32 | (−0.95,0.28) | −0.31 | 0.33 | (−0.95,0.34) | |
| MV2 | −0.42 | 0.23 | (−0.86,0.03) | −0.11 | 0.28 | (−0.66,0.43) | −0.95 | 0.40 | (−1.73,−0.16) | |
| MV3 | 1.06 | 2.75 | (−4.33,6.45) | 1.82 | 3.40 | (−4.85,8.49) | 2.50 | 4.74 | (−6.79,11.79) | |
MV0: unadjusted
Sample Size :1185 (Women 697; Men 488)
MV1: age, race, clinic site, sex
Sample Size :1185 (Women 697; Men 488)
MV2: age, sex, race, clinic site, BMI, cystatin C, physical activity, diabetes, education, calcium and vitamin D intake, medication use, smoking, alcohol and frailty
Sample Size :1185 (Women 697; Men 488)
MV3: age, sex, race, clinic site, BMI, cystatin C, physical activity, diabetes, education, calcium and vitamin D intake,, medication use, smoking, alcohol, frailty, protein and total energy (caloric) intake
Sample Size :1185 (Women 697; Men 488)
Sample size for total hip (sample size for other measurements of body composition were similar)
Table 5.
Body Mineral Density and Body Composition Measurements by Tyrosine Intake
| All | Women | Men | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| β | SE | 95%CI | β | SE | 95%CI | β | SE | 95%CI | ||
|
Total Hip BMD (g/cm2 ) |
MV0 | 0.42 | 0.39 | (−0.36, 1.19) | −0.63 | 0.40 | (−1.42, 0.16) | 0.50 | 0.54 | (−0.58, 1.55) |
| MV1 | −0.20 | 0.32 | (−0.82, 0.42) | −0.73 | 0.39 | (−1.50, 0.03) | 0.47 | 0.53 | (−0.56, 1.50) | |
| MV2 | −0.30 | 0.45 | (−1.18, 0.58) | −0.57 | 0.53 | (−1.6, 0.47) | 0.21 | 0.83 | (−1.42, 1.83) | |
| MV3 | 7.05 | 3.69 | (−0.18,14.28) | 6.12 | 4.37 | (−2.44, 14.69) | 10.17 | 6.75 | (−3.06, 23.40) | |
| Total body aBMD (g/cm2 ) | MV0 | 0.52 | 0.34 | (−0.15,1.19) | −0.28 | 0.33 | (−0.92,0.36) | 0.30 | 0.41 | (−0.51,1.10) |
| MV1 | −0.15 | 0.25 | (−0.65,0.35) | −0.42 | 0.32 | (−1.05,0.21) | 0.17 | 0.41 | (−0.63,0.97) | |
| MV2 | −0.72 | 0.38 | (−1.47,0.04) | −0.98 | 0.46 | (−1.89, −0.07) | −0.39 | 0.69 | (−1.74,0.96) | |
| MV3 | −0.87 | 3.16 | (−7.06,5.33) | −1.38 | 3.82 | (−8.87,6.12) | 2.07 | 5.60 | (−8.90,13.04) | |
|
Percent Fat |
MV0 | −0.68 | 0.22 | (−1.11,−0.25) | −0.15 | 0.23 | (−0.64,0.30) | −0.53 | 0.23 | (−0.97,−0.08) |
| MV1 | −0.27 | 0.16 | (−0.59,0.06) | −0.19 | 0.23 | (−0.64,0.27) | −0.36 | 0.23 | (−0.81,0.08) | |
| MV2 | −0.19 | 0.20 | (−0.58,0.19) | 0.06 | 0.26 | (−0.44,0.55) | −0.69 | 0.31 | (−1.29,−0.09) | |
| MV3 | 0.07 | 1.61 | (−3.09,3.22) | −0.21 | 2.10 | (−4.32,3.91) | 1.72 | 2.50 | (−3.18,6.61) | |
| Total Fat | MV0 | −0.53 | 0.21 | (−0.95,−0.12) | −0.21 | 0.29 | (−0.79,0.36) | −0.61 | 0.27 | (−1.14,−0.07) |
| MV1 | −0.37 | 0.20 | (−0.76,0.03) | −0.31 | 0.29 | (−0.87,0.26) | −0.44 | 0.27 | (−0.96,0.09) | |
| MV2 | −0.39 | 0.19 | (−0.76,−0.02) | −0.12 | 0.24 | (−0.59,0.35) | −0.86 | 0.31 | (−1.47,−0.24) | |
| MV3 | 0.19 | 1.56 | (−2.87,3.25) | −0.35 | 1.98 | (−4.22,3.51) | 2.47 | 2.55 | (−2.51,7.46) | |
| Percent Lean | MV0 | 0.68 | 0.22 | (0.25,1.11) | 0.15 | 0.23 | (−0.30,0.60) | 0.53 | 0.23 | (0.08,0.97) |
| MV1 | 0.27 | 0.16 | (−0.06,0.59) | 0.19 | 0.23 | (−0.27,0.64) | 0.36 | 0.23 | (−0.08,0.81) | |
| MV2 | 0.19 | 0.20 | (−0.19,0.58) | −0.06 | 0.26 | (−0.55,0.44) | 0.69 | 0.31 | (0.08,1.29) | |
| MV3 | −0.07 | 1.61 | (−3.23,3.09) | 0.21 | 2.10 | (−3.91,4.32) | −1.72 | 2.50 | (−6.61,3.18) | |
| Total Lean | MV0 | 0.51 | 0.23 | (0.06,0.96) | 0.03 | 0.15 | (−0.27,0.32) | 0.07 | 0.23 | (−0.37,0.52) |
| MV1 | −0.01 | 0.13 | (−0.26,0.24) | −0.06 | 0.15 | (−0.35,0.24) | 0.05 | 0.22 | (−0.38,0.47) | |
| MV2 | −0.12 | 0.18 | (−0.48,0.24) | −0.01 | 0.20 | (−0.40,0.37) | −0.30 | 0.36 | (−1.01,0.41) | |
| MV3 | −0.18 | 1.50 | (−3.11,2.76) | 1.37 | 1.61 | (−1.79,4.52) | −2.12 | 2.95 | (−7.91,3.66) | |
| Total Mass | MV0 | −0.02 | 0.31 | (−0.64,0.59) | −0.19 | 0.40 | (−0.96,0.59) | −0.53 | 0.42 | (−1.35,0.28) |
| MV1 | −0.38 | 0.28 | (−0.93,0.17) | −0.36 | 0.39 | (−1.12,0.40) | −0.39 | 0.40 | (−1.18,0.39) | |
| MV2 | −0.51 | 0.28 | (−1.05,0.04) | −0.14 | 0.34 | (−0.81,0.53) | −1.16 | 0.49 | (−2.12,−0.20) | |
| MV3 | 0.01 | 2.29 | (−4.47,4.50) | 1.02 | 2.81 | (−4.50,6.53) | 0.34 | 4.00 | (−7.49,8.18) | |
MV0: unadjusted
Sample Size :1185 (Women 697; Men 488)
MV1: age, race, clinic site, sex
Sample Size : 1185 (Women 697; Men 488)
MV2: age, sex, race, clinic site, BMI, cystatin C, physical activity, diabetes, education, calcium and vitamin D intake, medication use, smoking, alcohol and frailty
Sample Size :1185 (Women 697; Men 488)
MV3: age, sex, race, clinic site, BMI, cystatin C, physical activity, diabetes, education, calcium and vitamin D intake, medication use, smoking, alcohol, frailty, protein and total energy (caloric) intake
Sample Size :1185 (Women 697; Men 488)
Sample size for total hip (sample size for other measurements of body composition were similar)
Multiple imputation for missing data revealed no significant differences in outcome measures by AAA intake. There was no significant interaction of CRP concentration with the association of each AAA with incident hip fracture, BMD or any measurement of body composition (data not shown).
In post hoc analyses, in fully adjusted (M3) multivariable models, the lowest quartiles (compared to all other quartiles) of intakes of tryptophan (HR 1.33, 95% CI 1.03 to 1.70), phenylalanine (HR 1.28, 95% CI 1.10 to 1.64) and tyrosine (HR 1.32, 95% CI 1.03 to 1.69) were significantly associated with incident hip fractures. When these models were stratified by sex, significant associations with the lowest quartiles (compared with all other quartiles) of dietary intakes of tryptophan, phenylalanine and tyrosine were present in women (HR 1.48, 95% CI, 1.11 to 1.98; HR 1.4, 95%CI 1.05 to 1.87; and HR 1.41, 95% CI 1.06 to 1.89, respectively), but not in men (p≥0.77 for all). There were no significant differences in aBMD or body composition across any AAA quartiles (data not shown).
Discussion
The major finding of this study is that continuously modeled dietary intakes of AAA (i.e., tryptophan, phenylalanine, and tyrosine) are not associated with incident hip fracture, aBMD of the hip or any measures of body composition in elderly community-dwelling men and women. However, post hoc analyses suggested that participants with low dietary intakes of these AAA may be at heightened risk for hip fractures.
Few prior studies have examined the role of AAA in osteoporosis in humans. In support of our findings, that AAA may be beneficial for bone health, one randomized controlled study of 30 healthy men and post-menopausal women (age ≥ 51 years) reported that a relative five-fold gram-molar increase in intake of AAA compared with branched chain amino acids for two weeks increased calcium absorption (43). Further, a case control study reported that erythrocyte tryptophan concentrations were positively associated with lumbar spine and femoral neck BMD and bone histomorphometric indices of wall and trabecular thickness and mineral apposition rate (44). Notably, dietary intakes of all three of these AAA in CHS were above dietary reference intakes (DRI) for adults, even some among those in the lowest quartiles (45). Thus, we suspect that the association of low AAA intake with hip fractures may be even more substantial in the general elderly population. Low dietary protein has been associated with an increased risk of hip fractures. Aromatic amino acids are particularly enriched in protein (both vegetable and animal). In fact, subjects who are Vegans have lower bone density and fracture rates may be higher in those not ingesting adequate protein, calcium and vitamin D (46). Our studies suggest that independent of beneficial dietary protein effects on muscle and bone; aromatic amino acids in particular may provide additional protective effects for bone.
There are a number of strengths to this study. It is the first report in humans to examine the role of dietary AAA in osteoporosis including outcomes of hip fracture, hip aBMD and body composition. It includes both men and women, and both African Americans and Caucasians, although African Americans only constituted one in twenty of these participants and the results are not stratified by race.
There are also a number of limitations to consider. First, the findings were in elderly participants in the CHS study and may not be generalizable to other populations. Second, there is a potential misclassification of dietary intake of these AAA as diets are dynamic; thus, a one-time assessment with a FFQ may not accurately reflect changes in dietary habits over periods. Furthermore, DXA measurements were done five years after the dietary intakes were assessed and did not include longitudinal measurements. We did not have measurements of metabolites of these dietary AAA, which may be of particular importance. For example, tryptophan is metabolized by a number of pathways, of which the kynurenine pathway is of major interest as oxidative stress and inflammation upregulates indoleamine 2,3 deoxygenase (IDO) (47). Upregulation of IDO activity not only increases the generation of kynurenine, the oxidized tryptophan metabolite, but also locally depletes tryptophan concentrations. This in essence creates pockets of tryptophan deficiency, which can negatively impact mesenchymal stem cell anabolic capacity (48). In the Hordaland Health Study from Norway, serum measurements of kynurenine, a metabolite of tryptophan, was inversely associated with hip aBMD (49) and directly associated with hip fractures (50). Finally, despite a large sample of participants, confidence intervals were wide, suggesting high variability among aBMD and body composition measurements, which deserves reevaluation in future studies.
In conclusion, dietary intake of AAA was not significantly associated with incident hip fracture, areal bone mineral density of the hip or body composition in elderly, community-dwelling African American and Caucasian men and women. However, there may be a subset of elderly individuals with low intakes of AAA who are at higher risk for hip fracture. Future studies should investigate whether deficiencies of AAA are associated with increased risk of hip and other clinical fractures.
Supplementary Material
Acknowledgements
Drs. Carbone, Bůžková, Fink, Isales, Le, Shikany, Coughlin, and Robbins participated in the analysis/interpretation of the data, drafting and/or critical analysis of the manuscript and approved the final version of the submitted manuscript. Mattie Raiford participated in drafting the manuscript, approved the final version and assisted with interpretation of the data. Drs. Carbone, Bůžková and Robbins accept responsibility for the integrity of the data analysis.
The contents do not represent the views of the Department of Veterans Affairs or the United States Government.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org
Footnotes
Conflict of Interest: Brian Le, Petra Buzkova, John Robbins, Howard Fink, Mattie Raiford, Carlos Isales, James Shikany, Steven Coughlin and Laura Carbone have no conflict of interest.
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