Introduction
Hip fractures are common among elderly individuals and often have devastating sequelae. Dairy consumption has been promoted for fracture prevention because dairy products contain calcium, along with protein and phosphorus, and are sometimes fortified with vitamin D. However, prior systematic reviews have offered a conflicting and incomplete information for the beneficial effect of total dairy intake for hip fracture risk possibly due to the omission of certain studies and the failure to conduct careful dose-response analyses(Reference Bian, Hu and Zhang1–Reference Malmir, Larijani and Esmaillzadeh5).
Dairy consumption may carry potential adverse health consequences. Dairy products are the leading source of saturated fat in the US diet(Reference Hidayat, Du and Shi6), and dairy consumption has been associated with risk of cancer of the prostate and other organs(Reference O'Neil, Keast and Fulgoni7–Reference Larsson, Orsini and Wolk11), raising questions about the overall health effects of recommending this product group for fracture prevention.
We therefore undertook an evidence-based review and non-linear dose-response algorithmic meta-analysis of prospective studies to examine associations between dairy intake and hip fracture risk. Notably, we implemented a unique 1000+ model data-driven non-linear analysis algorithm to sequentially compare thousands of knots to determine the optimum non-linear dose-effect association for various dairy products, including milk, yoghurt, cheese and total dairy.
Methods
Search strategy
We searched the published scientific literature for prospective cohort studies of human participants reporting dairy or milk intake and the end point of incident hip fracture. Literature review was conducted in two phases, prior to July 2016, and after July 2016 until the end of 2021. In the first phase, two investigators identified articles published in English from 1946 to July 2016 through a search of MEDLINE (PubMed) and Google Scholar. We also identified additional articles from the reference lists of the extracted articles and reviews, and articles that cited extracted articles. The following terms were used for the MEDLINE search: (dairy[All Fields] OR milk [All Fields] OR human milk[All Fields] OR milk [MeSH Terms] OR yoghurt[All Fields] OR cheese[All Fields]) AND humans [MeSH Terms] AND (bone [All Fields] OR bones [All Fields] OR bone and bones [All Fields] OR bone [All Fields] OR fractures, bone [MeSH Terms] OR fractures [All Fields] OR bone fractures [All Fields] OR fracture [All Fields] OR accidental falls [MeSH Terms] OR dxa[All Fields] OR dexa[All Fields] OR (osteoporosis, postmenopausal[MeSH Terms] OR osteoporosis [All Fields]) OR bone diseases, metabolic[MeSH Terms] OR (bone[All Fields] OR osteopenia[All Fields]) OR (osteomalacia[MeSH Terms] OR osteomalacia[All Fields]) OR (bone density[MeSH Terms] OR bone[All Fields] OR bone density[All Fields] OR (bone[All Fields] AND mineral[All Fields] AND density[All Fields]) OR bone mineral density[All Fields])). Similar search terms were used for Google Scholar. No language restriction was applied.
In the second search phase, spanning July 2016 through December 2021, we conducted three parallel searches in effort to be more comprehensive, using two sets of Google Scholar searches, which limits results to <1000 results per search, and using MEDLINE to find additional prospective studies on dairy and risk of hip fractures. The following terms were used for the first Google Scholar search: (Dairy OR milk OR yoghurt OR cheese) AND (Bone OR fracture OR hip fractures OR dxa OR dexa OR osteoporosis OR bone diseases OR osteopenia OR osteomalacia OR bone mineral density). For the second wider Google Scholar search, we used the broader terms: (Dairy OR milk OR yoghurt OR cheese) AND (hip fracture OR fracture). We also conducted a search of MEDLINE between July 2016 through December 2021 using the following search terms: (dairy[All Fields] OR milk [All Fields] OR human milk[All Fields] OR milk [MeSH Terms] OR yoghurt[All Fields] OR cheese[All Fields]) AND humans [MeSH Terms] AND (bone [All Fields] OR bones [All Fields] OR bone and bones [All Fields] OR bone [All Fields] OR fractures, bone [MeSH Terms] OR fractures [All Fields] OR bone fractures [All Fields] OR fracture [All Fields] OR accidental falls [MeSH Terms] OR dxa[All Fields] OR dexa[All Fields] OR (osteoporosis, postmenopausal[MeSH Terms] OR osteoporosis [All Fields]) OR bone diseases, metabolic[MeSH Terms] OR (bone[All Fields] OR osteopenia[All Fields]) OR (osteomalacia[MeSH Terms] OR osteomalacia[All Fields]) OR (bone density[MeSH Terms] OR bone[All Fields] OR bone density[All Fields] OR (bone[All Fields] AND mineral[All Fields] AND density[All Fields]) OR bone mineral density[All Fields])). All search results were downloaded, cross-matched for de-duplication processing before assessment for eligibility within the phase of the search.
Study selection
We first conducted an initial screening of all titles. Abstracts were reviewed if the titles appeared to meet the inclusion criteria. Then, we assessed all potentially relevant studies based on text reviews. We included prospective studies of dairy intake and risk of hip fracture in humans and excluded literature reviews, clinical trials and studies with an ecological, case–control or cross-sectional design. We excluded papers using the criteria listed below. Papers were excluded based on the first applicable exclusion category: animal studies, no dairy consumption, no fracture, review, not prospective, correction, duplicate population or identified in prior search (if second search phase). And for those nearly qualified studies that report any/total fracture but not hip fracture, we emailed authors for additional information, but conditionally excluded such studies unless additional data is provided. We also excluded studies of individuals with pre-existing bone diseases and studies that did not report relative risks (RRs) or hazard ratios (HRs), dairy dose data and the corresponding 95 % confidence intervals (CIs).
Data extraction
Two authors (S.M. and K.B.) independently selected studies and performed the data extraction. To resolve any discrepancies, a third investigator (E.L.D.) was consulted, and any disagreements were settled by consensus of all three authors. The primary exposure variables were milk, yoghurt, cheese, cream, soured milk and yoghurt, total dairy without cream and total dairy with cream consumption. Total dairy with cream included milk, yoghurt, frozen yoghurt and cheese. The outcome of interest was risk of hip fracture. Data extraction was conducted using a standardised data collection form. The following characteristics of the identified articles were recorded: first author, year of publication, cohort name, study population, study design, country, mean/median age, adjustment for body mass index (BMI), adjustment for energy intake (kilocalories), industry funding, percentage of women, follow-up duration, calcium and vitamin D supplement use, and baseline dietary calcium and vitamin D levels, where available, as well as the quality measures noted below.
When data were incomplete or missing, we contacted the authors to obtain additional data. We also attempted to contact authors who we believed were likely to have data on dairy intake and fracture risk based on their prior publications, and obtained additional updated data from the Nurses’ Health Study, Health Professionals Follow-up Study, Swedish Mammography Cohort and the Framingham Offspring Study through personal communication with study authors or research staff. Other authors of cohort studies with potentially relevant data were contacted, but none provided dairy and hip fracture risk data that could allow for their inclusion.
Quality measures
Study reports were qualitatively examined for means of dietary assessment, diagnosis and fracture assessment, sample size and statistical measures.
Statistical analysis
To determine whether results indicated non-linear or linear relationships between dairy product consumption and fracture risk, the linearity of associations was first examined using spline analyses and dose-response meta-regressions. For non-linear analysis, we comprehensively assessed the dose across the entire dairy consumption spectrum for non-linear associations, for both single-knot and dual-knot splines for comparative model analysis, at individual 25 g intervals, and used data-driven algorithms to select for the optimal single spline. If a single-knot spline was found superior to linear coefficient model, then upon identification of the optimal single spline, double-spline dose models were tested straddling around the single spline to further assess for potential model superiority. Splined variables were created with the use of MKSPLINE in STATA version 13.1 (College Station, TX). Goodness-of-fit tests and chi-square statistics were used to determine the most appropriate knot points and maximal goodness of fit to assess the fit of potential non-linear relationships and to determine the best dose-response inflection point of any potential non-linear association across a range of intakes. The Greenland and Longnecker dose-response generalised least-square meta-regression analysis using GLST command in STATA was used to derive the dose-response RRs, P-values and 95 % CIs(Reference Moher, Liberati and Tetzlaff12). For non-linear associations, the shapes of the associations within individual studies were assessed via repeated modelling of different knot points in order to determine potential splines for best model fit, indicating the optimal non-linear spline model. The pooled non-linear dose curves were visualised using Spaghetti Plots, as previously applied(Reference Greenland and Longnecker13). Where non-linearity was not indicated, forest plots were produced to portray linear dose-response relationships and corresponding 95 % CIs via random-effects models. Begg's funnel plots and Begg's test are used to assess potential publication bias. To assess statistical heterogeneity, Cochran's Q test was conducted and the I 2 statistic was calculated, representing the percentage of total variation attributable to between-study heterogeneity(Reference Bauer, Hankinson and Bertone-Johnson14). Potential publication bias was assessed with Egger's test. Two-sided P-values <0⋅05 were considered to be statistically significant.
Results
The Phase 1 PubMed and the Google Scholar searches prior to July 2016 yielded 8781 citation titles for review that yielded 11 relevant studies, two of which were identified from the search of references of the retrieved publications and subsequent author contact. The Nurses’ Health Study, Health Professionals Follow-up Study, Swedish Mammography Cohort and Framingham Offspring Study were among the studies that also provided their updated data through personal communication to the senior author. The Phase 2 set of searches of PubMed and Google Scholar from July 2016 to December 2021 yielded 2218 citation titles for review, of which 2 were new relevant and eligible articles, not previously included or captured in personal communications. Altogether, across the two phases of searches, thirteen articles were included in this analysis. The flow of these articles is described in Fig. 1.
Fig. 1. Flowchart diagram showing the number and disposition of articles assessed for eligibility and included in the review from searches of PubMed and Google Scholar.
Characteristics of included studies
We based our analyses on 13 studies from 16 unique study populations involving 486 950 participants and 15 320 fractures. Additional data from the Swedish Mammography cohort(Reference Higgins and Thompson15) (Michaelsson, personal communication, November 2017) added information on 1568 additional hip fractures beyond the original published study data set(Reference Michaelsson, Wolk and Eva Lemming16), for an updated total of 5827 hip fractures from that cohort.
Although all studies assessed dietary intake by food frequency questionnaires, repeat measurements of dietary intake were available only in the Nurses’ Health Study, Health Professionals Follow-up Study and Swedish Mammography Cohorts. All other cohorts collected dietary data only at baseline. Diagnosis of fracture was based on self-report confirmed by medical records, death certificates, radiographic and operative report or events validated through linkage with national patient registries.
Five studies provided data that were not separated by gender(Reference Michaëlsson, Wolk and Langenskiöld17–Reference Bergholdt, Larsen and Varbo22). Two cohorts included only men(Reference Michaelsson, Wolk and Eva Lemming16,Reference Sahni, Mangano and Tucker23) . Four cohorts included only women(Reference Higgins and Thompson15,Reference Sahni, Mangano and Tucker23–Reference Huang, Himes and McGovern25) , and two provided data for men and women separately(Reference Cumming, Cummings and Nevitt26,Reference Feskanich, Willett and Stampfer27) . One study provided data pooled by gender and also separately for women(Reference Meyer, Pedersen and Loken28). Seven studies were conducted in the USA(Reference Feart, Lorrain and Ginder Coupez19–Reference Huang, Himes and McGovern25), two in Sweden(Reference Higgins and Thompson15,Reference Michaelsson, Wolk and Eva Lemming16) , two in Norway(Reference Cumming, Cummings and Nevitt26,Reference Feskanich, Willett and Stampfer27) , one in Denmark(Reference Bergholdt, Larsen and Varbo22) and one each in Japan(Reference Cumming, Cummings and Nevitt26), France(Reference Benetou, Orfanos and Zylis18) and Europe(Reference Michaëlsson, Wolk and Langenskiöld17). Of the thirteen studies included in this meta-analysis, three reported receiving industry funding(Reference Benetou, Orfanos and Zylis18,Reference Feart, Lorrain and Ginder Coupez19,Reference Lousuebsakul-Matthews, Thorpe and Knutsen21) , and one study with partial industry funding for a doctoral student(Reference Bergholdt, Larsen and Varbo22). Table 1 shows the baseline characteristics for all included studies.
Table 1. Characteristics of studies selected for inclusion in the review
Total dairy consumption and hip fracture
Among the eight cohorts that investigated associations between total dairy intake and hip fracture risk, six found no association (Health Professionals Follow-up Study(Reference Sahni, Mangano and Tucker23), Adventist Health Study-2(Reference Sahni, Tucker and Kiel20), Three-City Study(Reference Benetou, Orfanos and Zylis18), Framingham Offspring Study(Reference Feart, Lorrain and Ginder Coupez19), EPIC Elderly Network on Aging and Health(Reference Michaëlsson, Wolk and Langenskiöld17), NHANES-1 Epidemiologic Follow-up study(Reference Feskanich, Meyer and Fung24)). Two reported decreased risk of hip fracture with increased dairy intake (Feskanich, personal communication, October 2016 and Michaelsson, personal communication, November 2017), albeit only with moderate dairy intake in one of these (Michaelsson, personal communication, November 2017).
Although there were eight study populations for which data on total dairy intake were available (Nurses’ Health Study(Reference Sahni, Mangano and Tucker23), Health Professionals Follow-up Study(Reference Sahni, Mangano and Tucker23), Swedish Mammography Cohort(Reference Higgins and Thompson15), Adventist Health Study-2(Reference Sahni, Tucker and Kiel20), The Three-City Study(Reference Benetou, Orfanos and Zylis18), Framingham Offspring Cohort(Reference Feart, Lorrain and Ginder Coupez19), EPIC Elderly Network on Aging and Health(Reference Michaëlsson, Wolk and Langenskiöld17), NHANES-1 Epidemiologic Follow-up study(Reference Feskanich, Meyer and Fung24)) (Feskanich, personal communication, October 2016 and Michaelsson, personal communication, November 2017), we first conducted an assessment of potential non-linearity of the association among the eight studies with multiple dose-response data points per study (19 total data points). These included the (Nurses’ Health Study(Reference Sahni, Mangano and Tucker23), Health Professionals Follow-up Study(Reference Sahni, Mangano and Tucker23), Swedish Mammography Cohort(Reference Higgins and Thompson15), Adventist Health Study-2(Reference Sahni, Tucker and Kiel20), Framingham Offspring Cohort(Reference Feart, Lorrain and Ginder Coupez19), EPIC Elderly Network on Aging and Health(Reference Michaëlsson, Wolk and Langenskiöld17)) (Feskanich, personal communication, October 2016 and Michaelsson, personal communication, November 2017).
Across the range of doses, no spline knot point yielded significant evidence of a non-linear association, with 100 g/d of total dairy being the closest potential spline point, which was not significant for non-linearity (P = 0⋅19). Thus, we analysed all available studies of total dairy and hip fracture in linear dose response fashion. Pooling of the studies in a linear dose increment, expressed per 250 g/d, yielded no significant association between total dairy consumption and hip fracture risk (RR 0⋅97, 95 % CI 0⋅93, 1⋅00). There was no significant heterogeneity, with I 2 = 34⋅5 % and overlapping null (95 % CI 0, 71 % and P = 0⋅15). The forest plot is shown in Fig. 2. No publication bias trend was observed (Egger's Test P = 0⋅66).
Fig. 2. Forest plot for the association of total dairy intake with risk of hip fracture.
Milk intake and hip fracture
For milk intake, one study (Michaelsson, personal communication, November 2018)(Reference Higgins and Thompson15) showed elevated risk of hip fracture with increased milk intake, seven showed no association(Reference Michaelsson, Wolk and Eva Lemming16,Reference Benetou, Orfanos and Zylis18,Reference Feart, Lorrain and Ginder Coupez19,Reference Lousuebsakul-Matthews, Thorpe and Knutsen21,Reference Bergholdt, Larsen and Varbo22,Reference Huang, Himes and McGovern25,Reference Meyer, Pedersen and Loken28) , and three studies (Nurses’ Health Study(Reference Sahni, Mangano and Tucker23), Health Professionals Follow-up Study(Reference Sahni, Mangano and Tucker23) and middle-aged Norwegian cohort(Reference Cumming, Cummings and Nevitt26)) (Feskanich, personal communication, October 2016) showed lower risk with increased milk intake.
We conducted an assessment of potential non-linearity of the association among the studies with multiple dose-response data points per study (fifty-nine data points total). Across the ranges of different doses algorithmically tested, a strong spline knot point yielded significant strongest evidence of a non-linear association, with 400 g/d being the most robust dose-risk inflection point (P for non-linearity < 0⋅0001); double-knot spline models straddling 400 g/d were not superior to a single knot at 400 g/d. Thus, we analysed the fourteen populations with milk and hip fracture data in a non-linear dose response fashion. Up to a daily dose of 400 g/d, the results showed that milk intake was associated with increased fracture risk, with a dose effect of 7 % increased risk per 200 g/d of milk (RR 1⋅07, 95 % CI 1⋅05, 1⋅10; P < 0⋅0001). At 400 g/d of milk intake, compared to 0 g/d, there was a 15 % higher risk of hip fracture (RR 1⋅15, 95 % CI 1⋅09, 1⋅21, P < 0⋅0001). However, above 400 g/d of milk, although there is a slight attenuation in the higher risk with a dose trend effect of a −4⋅5 % per 200 g/d of milk (RR 0⋅955, 95 % CI 0⋅92, 0⋅99, P = 0⋅007) compared to the risk peak of 400 g/d – milk consumption nevertheless continued to exhibit elevated risk of hip fracture with intakes up to 750 g/d. In no range of observed milk intake did the analysis show any significantly lower risk of hip fracture compared to 0 g/d. The test of heterogeneity yielded a between-study variance of 0 in all models, indicating no significant heterogeneity. Results are shown in the Spaghetti Plot of Fig. 3.
Fig. 3. Spaghetti plot for the association of milk intake with risk of hip fracture. Each thin gray-colored ‘noodle’ of the spaghetti plot represents an individual study. The pooled non-linear association is represented by the red curve, with 95 % confidence intervals in blue.
Yoghurt, fermented milk, cheese and hip fracture
A smaller number of studies examined yoghurt, fermented milk or cheese intake in relation to hip fractures, and none of these studies controlled for socioeconomic status (SES). Because of the limited number of studies, we did not perform a non-linear analysis, which requires more datapoints for reliable computation; and none were apparent via tested knots. Thus, pooling the five studies(Reference Higgins and Thompson15,Reference Michaelsson, Wolk and Eva Lemming16,Reference Benetou, Orfanos and Zylis18,Reference Feart, Lorrain and Ginder Coupez19,Reference Lousuebsakul-Matthews, Thorpe and Knutsen21) (Michaelsson personal communication, November 2017) of yoghurt and fermented milk intake with hip fracture, the linear analysis per 250 g/d yielded an inverse association of 15 % lower hip fracture risk (RR 0⋅85, 95 % CI 0⋅82, 0⋅89). The model did not reveal significant heterogeneity, with between-study variance of 0, P = 0⋅60 (Fig. 4). No publication bias trend was observed (Egger's Test P = 0⋅16). Similarly, pooling the five studies of cheese intake and hip fracture in linear dose analysis found that cheese intake per 43 g/d (~1 serving/day) was associated with an inverse association of 19 % lower hip fracture risk (RR 0⋅81, 95 % CI 0⋅72, 0⋅92), while one study without precise cheese dose (any versus no cheese) found no association for cheese and hip fracture(Reference Bergholdt, Larsen and Varbo22). Heterogeneity was not significant, with I 2 = 52 (95 % CI 0–82, P = 0⋅08) (Fig. 5). No publication bias trend was observed (Egger's Test P = 0⋅37).
Fig. 4. Forest plot for the association of yoghurt intake with risk of hip fracture.
Fig. 5. Forest plot for the association of cheese intake with risk of hip fracture.
Discussion
In the present analysis, there was no significant relationship between overall dairy intake and hip fracture risk. These findings, derived from the most complete data set and most comprehensive and algorithmically driven meta-analysis of prospective cohorts to date, contradict the findings of earlier meta-analyses for milk(Reference Bian, Hu and Zhang1,Reference Bischoff-Ferrari, Dawson-Hughes and Baron2,Reference Kanis, Johansson and Oden4–Reference Hidayat, Du and Shi6) .
Among dairy subfractions, the largest body of data was for milk intake, which was directly and significantly associated with risk of hip fracture. This risk was moderated at intakes above 400 g/d, but at no level of milk intake was there a suggestion of a significant protective association between milk and fracture risk.
There were noteworthy differences in findings between cohorts in the US and Swedish Mammography Cohort. However, even with sensitivity exclusion of the large Swedish Mammography cohort, milk still did not exhibit any inverse association with fractures. Moreover, the cohort of Swedish men and two cohorts in Norway also were in agreement with the overall findings on milk and fracture. Nevertheless, it is important to consider potential factors that could explain the observed variability. Although all studies included in this review used similar designs and diagnostic criteria, there were differences in age, body weight and vitamin D exposure, which may have influenced their findings.
Age
The three cohorts that reported protective effects of milk intake on hip fracture risk (middle-aged Norwegian cohorts, Nurses’ Health Study and Health Professionals Follow-up Study) had participants with mean baseline ages ranging between 47 and 58 years, whereas mean baseline age of participants in all other cohorts ranged between 53⋅5 and 77 years.
Body weight
In the Nurses’ Health Study and Health Professionals Follow-up Study, the inverse associations between dairy consumption and hip fracture risk were mainly limited to those with larger BMI(Reference Sahni, Mangano and Tucker23). Obesity is much more common in the US than in other countries(Reference Feskanich, Singh and Willet31), affecting approximately 40 % among US adults >20 years old, compared with approximately 19 % of adults in Sweden(Reference Feskanich, Singh and Willet31,Reference Hales, Fryar and Carroll32) .
Vitamin D
Vitamin D enhances calcium absorption(Reference Bonjour and Lecerf33,Reference Lamberg-Allardt, Brustad and Meyer34) . It is noteworthy that the US-based Nurses’ Health Study, which reported baseline intakes of 9⋅7 μg vitamin D and 1060 mg calcium per day, found a protective effect of milk intake, while the Swedish Mammography Cohort, which reported baseline intakes of 4⋅6 μg vitamin D and 916⋅5 mg calcium per day, found increased hip fracture risk with increased milk intake.
In the US, all milk is fortified with vitamin D and is the single biggest contributor to vitamin D intakes (58 % in men, 39 % in women)(Reference Christakos35). In Sweden, only low-fat milk are fortified(Reference O'Mahony, Stepien and Gibney36) (although they remain significant contributors to vitamin D intake)(Reference Spiro and Buttriss37). In Norway, milk is not routinely fortified with vitamin D(Reference Burgaz, Akesson and Oster38). Milk's role in vitamin D status is not entirely straightforward, however. Despite vitamin D fortification, dairy calcium can suppress vitamin D activation, depressing circulating levels of 1,25-dihydroxyvitamin D(Reference Chan, Stampfer and Ma8).
These observations suggest that discordant findings among studies may be in part attributable to differences in age, participant weight and vitamin D fortification. Although differences in fat content of milk may seem to be an additional possible explanatory factor for between-study differences, analyses of fracture risk by fat content did not yield different effects (Michaelsson, personal communication, November 2017)(Reference Higgins and Thompson15,Reference Michaelsson, Wolk and Eva Lemming16) .
The mechanisms behind potentially higher risk of hip fracture with milk intake are not entirely clear. d-galactose, a breakdown product of lactose, has been linked to oxidative stress and inflammation, potentially increasing the risk of fracture and mortality(Reference Higgins and Thompson15,Reference Michaelsson, Wolk and Eva Lemming16) . Higher levels of d-galactose in milk, compared with lower or non-existent levels in cheese, may partly explain positive associations of milk and inverse association of cheese with hip fracture risk reported in the Swedish Mammography Cohort(Reference Higgins and Thompson15). Furthermore, milk intake during adolescence modestly increases height, a risk factor for fracture(Reference Feskanich, Bischoff-Ferrari and Frazier39), which a study of teenage milk intake yielded higher hip fracture risk in men, and no effect in women in later adulthood(Reference Feskanich, Bischoff-Ferrari and Frazier39). Similarly, a Canadian study also found no association between childhood milk consumption and fracture risk(Reference Allison, Birken and Lebovic40).
Fewer studies examined relationships between yoghurt and cheese intake and hip fracture risk, but overall these studies indicated general inverse relationships for yoghurt and hip fracture, and possibly for cheese, though unclear. A seemingly protective association with cheese may be surprising, particularly given that cheese is high in sodium, a micronutrient strongly associated with loss of bone density(41). The interpretation of this finding is complicated by the fact that the included studies did not adjust for SES except those by Michaelson, Holvik et al. and Feart et al. In the US and Europe, yoghurt and cheese consumption is positively associated with SES, while SES appears to have a neutral or negative association with milk consumption(Reference Devine, Criddle and Dick42–Reference Sanchez-Villegas, Martınez and Prattala45). Indeed, the one Danish prospective study(Reference Bergholdt, Larsen and Varbo22) that did adjust for education level did not find any inverse association for milk and hip fracture risk.
Strengths
Our study has notable strengths. It includes a larger number of prospective studies that were available for previous meta-analyses of dairy-fracture risk(Reference Bian, Hu and Zhang1,Reference Sahni, Mangano and Tucker23,Reference Feskanich, Willett and Stampfer27,Reference Deshmukh-Taskar, Nicklas and Yang46–Reference Feskanich, Willett and Colditz48) , and we also included de novo updated estimates from personal communications with Swedish collaborators (Michaelson, personal communication, November 2017). Furthermore, our study included a detailed algorithmically driven dose-response meta-regression incorporating non-linear splines and accounting for differing reference intake levels, which together allowed us to algorithmically identify significant non-linear associations for milk intake that had not been previously identified. Furthermore, our results of null associations for total dairy with hip fracture risk are corroborated by a more recent study(Reference Webster, Greenwood and Cade49).
Limitations
This study also has limitations. Data on dairy consumption were collected using food frequency questionnaires, which may have minor variation in the interpretation of one glass of milk. Data on incident hip fractures were obtained through self-reports in some of the studies included. A large proportion of people are discharged to a nursing facilities after suffering from a hip fracture and mortality after hip fracture is high, which may have contributed to lower reports of fracture events and loss to follow-up. Although SES is sometimes associated with cheese and yoghurt intake, however, SES was explored in the Nurses’ Health Study and HPFS, which have little SES confounding due to the relatively homogeneous populations of health professionals. That said, there may be other non-linear associations that were not detected due to limited available studies and data points. While the Swedish Mammography Cohort was an influential milk study, it was the most comprehensive study of its kind, and its prominence and large size (and simultaneous publication with the Cohort of Swedish Men in the same BMJ paper) indicates that it was unlikely to have be suffered file-drawer publication bias that smaller studies tend to suffer, but which large studies don't. Plus, an analysis without the Swedish Mortality Cohort (SMC) still exhibited non-linearity, albeit smaller slopes. Furthermore, the SMC study's exclusion did not materially change the results for total dairy, yoghurt or cheese, with risk of hip fracture. Moreover, additional follow-up data from the SMC with ~1500 more hip fracture cases only further strengthened the findings. Finally, our study lacked data on dairy intake and hip fracture risk in children; it is possible dairy may have beneficial effects on paediatric populations, but this requires a careful future evaluation of the dairy-bone density literature, given the lack of studies with hip fracture end points in children.
Conclusions
Overall, increasing milk intake is associated with significantly increased risk of hip fracture, while intake and risk have inverse relationships for yoghurt and cheese intake. Because of the divergence in dairy products, total dairy intake is not associated importantly with risk of hip fracture.
Acknowledgements
The authors appreciate the feedback of Neal Barnard, and the extra efforts of Diane Feskanich in providing data support. The authors are grateful to Karl Michaelsson and Liisa Byberg for providing additional data from the Swedish Mammography Cohort and to Diane Feskanich for providing detailed numbers from the NHS and HPFS cohorts to allow complete dose-response meta-analyses. And acknowledge the support of research assistant Maya Chavez.
All authors contributed to development of the study design and data collection. S. M. and E. L. D. conducted data quality control. E. L. D. conducted analysis. S. M. and E. L. D. wrote the first draft with contributions from V. S. M. and K. B. All authors reviewed and commented on subsequent drafts and provided final approval of the manuscript.
E. L. D., S. M. and K. B. had received consultancy fees from the Physicians Committee for Responsible Medicine. V. S. M. is supported by 2R01HL060712-14, NIH/NHLBI ‘Dietary Patterns and Risk of Cardiovascular Disease’, has received research support from the Peanut Institute, was a pro bono retained expert for the Center for Science in the Public Interest in litigation related to sugar-sweetened beverages, and was a consultant for the City of San Francisco in litigation related to warning labels on soda.
This study was conducted according to the guidelines laid down in the Declaration of Helsinki and all procedures involving research study were reviewed and approved with exemption by the Harvard Human Subjects Review Board. Because of the literature review and meta-analysis nature of the study, written informed consent was not needed. E. L. D. conducted the research during 2016–2020 while a researcher at the Harvard SPH.
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