A Missed Opportunity in Bone Health: Vitamin D and Calcium Use in Elderly Femoral Neck Fracture Patients Following Arthroplasty

Abstract

Introduction:

Introduction: Adequate calcium and vitamin D from diet and supplementation is recommended for elderly hip fracture patients. Using data from the multinational hip fracture arthroplasty trial (HEALTH), we determined the proportion of patients who consistently took vitamin D and calcium and which characteristics/prescribing practices were associated with consistency of supplement use.

Methods:

HEALTH is a multicenter randomized trial of elderly hip fracture patients treated with hemi-arthroplasty and total hip arthroplasty. Patients were categorized as consistent users, inconsistent users, or nonusers of calcium and vitamin D. We used multinomial regression to determine the characteristics associated with calcium and vitamin D use.

Results:

603 HEALTH participants were included in the analysis. 34.7% of patients never took vitamin D within 12 months after surgery, 26.2% took vitamin D inconsistently, and 39.1% took vitamin D consistently. 36.0% of patients never took calcium within 12 months after surgery, 28.4% took calcium inconsistently, and 35.7% took calcium consistently. There was great variation in prescribed/recommended doses. Compared to nonusers, consistent users of the supplements were more likely to be female, North American, prescribed/recommended vitamin D and/or calcium postoperatively, and presented to a facility with comprehensive fragility fracture protocols.

Conclusions:

A low proportion of elderly hip fracture patients are consistently taking vitamin D and calcium, which may contribute to poorer bone health. Surgeons should be educated to prescribe/ recommend vitamin D and calcium, institutions should develop comprehensive fragility fracture protocols and patient education strategies to ensure that patients with osteoporosis receive bone health management beyond fracture care.

Introduction

The refracture rate in patients with hip fragility fractures is very high, with up to 14% of patients sustaining a second fragility fracture.¹ Vitamin D and calcium supplementation are frequently advised in elderly populations, especially relating to prevention of, and after, hip fractures and to reduce the very high rate of refractures in this population.^2,3 Vitamin D and calcium supplementation have been shown to have positive effects including increasing 25(OH)D serum levels,⁴ improving bone mineral density,^5,6 and reducing the risk of falls.^7,8 Additionally, studies have shown that calcium and vitamin D supplementation is a cost-effective method of preventing future fragility fractures in patients who have sustained a hip fracture.^9,10

The current Osteoporosis Canada clinical practice guidelines recommend routine vitamin D supplementation with 800 to 1000 IU daily for healthy adults older than 50 years, although up to 2000 IU per day may be necessary for higher risk adults.² Additionally, the Canadian guidelines state that calcium intake from diet and supplements should be 1200 mg daily. Guidelines in the United States and United Kingdom are similar, recommending at least 1000 mg of calcium and 800 IU of vitamin D.^3,11 Despite these guidelines, a recent survey of orthopedic surgeons in Canada and the United States found a lack of consensus on prescribing practices for calcium and vitamin D in fracture patients, as well as a large variability in dosing regimens.¹²

Adherence to calcium and vitamin D supplementation has been shown to vary greatly in previous studies, from 20% to over 60%.^13-15 As with other pharmacological therapies, treatment adherence is likely to have an important influence on the efficacy of calcium and vitamin D supplementation. For example, studies in highly controlled populations with high compliance have shown benefits of calcium and vitamin D supplementation, whereas studies in community settings with less strict controls on adherence show fewer benefits.^16,17 An analysis of elderly patients with femoral neck fractures treated with internal fixation found that over half of patients (54.3%) were either not taking or not consistently taking vitamin D following their fracture.¹⁸

The ongoing multicenter HEALTH trial¹⁹ (randomized controlled trial in elderly femoral neck fracture patients comparing hemi-arthroplasty and total hip arthroplasty) provides a unique opportunity to determine whether elderly hip fracture patients are consistently taking vitamin D and calcium supplements following a hip fracture treated with joint replacement in a clinical trial. It also provides an opportunity to explore factors associated with the consistent use of vitamin D and calcium supplementation. Using data from this trial, the objectives of the current study are (1) to determine the proportion of patients who consistently take vitamin D and/or calcium following arthroplasty, (2) to describe which doses of vitamin D and calcium are frequently used among patients enrolled in HEALTH, and (3) to determine which baseline characteristics and management/prescribing practices were associated with consistency of vitamin D and calcium use.

Methods

Health Study Overview

The HEALTH trial (NCT00556842) is a multicenter randomized controlled trial that compares hemi-arthroplasty versus total hip arthroplasty in patients older than 50 years with displaced femoral neck fractures. Sixty-one clinical sites in 10 countries in North America, Europe, and Australia are participating in the HEALTH trial. The primary objective of the HEALTH trial was to determine the rates of unplanned secondary procedures within 2 years in individuals with displaced femoral neck fractures treated with hemi-arthroplasty versus total hip arthroplasty. Secondary objectives include comparing health-related quality of life and health outcome measures, mortality, and hip-related complications in the 2 treatment groups. Patients were assessed clinically at 1 and 10 weeks and 6, 9, 12, 18, and 24 months postsurgery. This trial is coordinated by the Centre for Evidenced-Based Orthopaedics (McMaster University) and has been approved by the Hamilton Integrated Research Ethics Board (#06-151), as well as all participating clinical sites’ research ethics boards/institutional review boards.

Vitamin D and Calcium Supplementation Substudy

All patients enrolled in HEALTH were asked whether they take vitamin D and calcium supplementation, and the dose of each, at the study follow-up visits. To be included in this substudy, patients had to attend at least 3 of the 5 study follow-up visits within 12 months and had to have reached at least the 12-month study follow-up visit. Based on their reported frequency of vitamin D and calcium supplementation in the first 12 months of follow-up, patients were categorized as either consistent users (positive report at 4-5/5 visits), inconsistent users (positive report at 1-3/5 visits), or nonusers (positive report at 0/5 visits) of vitamin D and/or calcium.

Vitamin D and Calcium Supplementation Prescribing Practices at Clinical Sites

At the first postoperative visit, the HEALTH trial protocol recommended that surgeons prescribe 1000 IU of vitamin D and 600 mg of calcium and that surgeons initiate investigation and treatment of osteoporosis as recommended by a local osteoporosis expert/consultant. Clinical sites had different standards of care for prescribing vitamin D and calcium, which were acceptable to the HEALTH protocol. To learn more about these practices, principal investigators and research coordinators at participating clinical sites were asked to describe if and how vitamin D and calcium were prescribed or recommended in elderly arthroplasty patients at their hospital/clinic, for example, whether there is a standardized protocol for managing fragility fractures at their site.

Data Analysis

Patient characteristics were summarized using descriptive statistics. Categorical baseline variables were summarized as counts and percentages. Continuous baseline data were summarized as means and standard deviations. The doses of vitamin D and calcium used were summarized using the median, interquartile range, and mode. Prescription/recommendation practices were also summarized using descriptive statistics as described above.

Multinomial logistic regression models were used to determine whether the following independent variables were associated with consistency of vitamin D and calcium supplementation: (1) age, (2) sex, (3) location of hospital (North America vs Europe and Australia), (4) a prescription or recommendation to take vitamin D and/or calcium upon hospital discharge, and (5) management practices (comprehensive pathway/protocol vs some protocol vs no standard protocol/unknown practices). Odds ratios (ORs) with 95% confidence intervals (CIs) were reported to compare nonusers, inconsistent users, and consistent users for both calcium and vitamin D. Statistical significance was determined at α = .05. All statistical analyses were performed using SPSS version 24.

Results

Patient Demographics

Of the 824 HEALTH participants who had reached their 12-month visit, 603 were included in this analysis. We excluded data from the 100 patients who had died prior to their 12-month visit and the 121 participants who did not have at least 3 postoperative visits. The mean age of the study participants was 78.6 years (standard deviation: 8.8), and most participants were female (73.1%). The majority of patients were enrolled at clinical sites in North America (244, 40.5%) and Europe (325, 53.9%; Table 1).

Table 1.

Patient Demographics.

Characteristic	N = 603, n (%)
Age, mean (SD)	78.6 (8.8)
Sex
Female	441 (73.1)
Male	162 (26.9)
BMI
Underweight	32 (5.3)
Normal weight	294 (48.8)
Overweight	194 (32.2)
Obese	71 (11.8)
Missing	12 (2.0)
Location
Canada	133 (22.1)
The Netherlands	128 (21.2)
United States	112 (18.6)
Norway	107 (17.7)
Spain	73 (12.1)
Australia	33 (5.5)
United Kingdom	17 (2.8)
ASA classification
1	14 (2.3)
2	219 (36.3)
3	241 (40.0)
4	36 (6.0)
Missing	93 (15.4)
Employed	23 (3.8)
Ethnicity
White	577 (95.7)
Black	9 (1.5)
Asian	6 (1.0)
Hispanic/Latino	5 (0.8)
South Asian	3 (0.5)
Middle Eastern	3 (0.5)
Mechanism of injury
Fall from standing	589 (97.7)
Spontaneous	12 (2.0)
Other	2 (0.3)
Level of the fracture line
Subcapital	398 (66.0)
Midcervical	183 (30.3)
Basal	22 (3.6)
Garden classification
Garden I	6 (1.0)
Garden II	19 (3.2)
Garden III	219 (36.3)
Garden IV	359 (59.5)
Pauwel classification
Type I	34 (5.6)
Type II	332 (55.1)
Type III	235 (39.0)
Missing	2 (0.3)
Additional fractures	32 (5.3)
Additional injuries	29 (4.8)
Taking bisphosphonates at baseline	44 (7.3)
Taking other osteoporosis medications at baseline	20 (3.3)
Vitamin D prescribed/recommended postoperatively	456 (75.6)
Calcium prescribed/recommended postoperatively	435 (72.1)

Abbreviation: SD, standard deviation. ASA, American Society of Anethesiologists.

Vitamin D and Calcium Supplementation

Two-hundred nine (34.7%) patients reported never taking vitamin D within the first 12 months after surgery, 158 (26.2%) reported taking vitamin D inconsistently, and 236 (39.1%) reported taking vitamin D consistently (Table 2). Two hundred seventeen (36.0%) patients reported never taking calcium within the first 12 months after surgery, 171 (28.4%) reported taking calcium inconsistently, and 215 (35.7%) reported taking calcium consistently (Table 2). Vitamin D and calcium use consistency was highly correlated (Spearman ρ: .861; P < .001). There were 197 (32.7%) participants who consistently used both calcium and vitamin D and 194 (32.2%) participants who consistently did not use calcium nor vitamin D.

Table 2.

Consistency of Vitamin D and Calcium Use.

	Vitamin D			Total
	Nonuser	Inconsistent User	Consistent User
Calcium
Nonuser	194	12	11	217
Inconsistent user	12	131	28	171
Consistent user	3	15	197	215
Total	209	158	236	603

Vitamin D and Calcium Doses

Of the patients who took vitamin D at 1 visit or more, 24 different doses of vitamin D (21 daily and 3 weekly) were identified. The most common doses of vitamin D included 1000 IU (464/1147 visits), 800 IU (409/1147 visits), and 2000 IU (104/1147 visits). The median daily dose taken was 1000 IU (Q1-Q3: 800-1000 IU; Table 3). The lowest daily dose taken was 200 IU and the highest daily dose taken was 8000 IU. Some patients received a weekly dose as opposed to daily. The lowest weekly dose taken was 5000 IU (∼714 IU daily) and the highest weekly dose taken was 50 000 IU (∼7140 IU daily; Table 3).

Table 3.

Commonly Prescribed Vitamin D and Calcium Doses.

Vitamin D Dosesa	Number of Visits (%)
Daily doses
Under 800 IU	51 (4.5)
800-999 IU	414 (36.1)
1000-1499 IU	479 (41.8)
1500-1999 IU	19 (1.7)
2000-2999 IU	108 (9.4)
3000 IU or more	22 (1.9)
Weekly loading doses
5000 IU	13 (1.1)
10 000 IU	19 (1.7)
50 000 IU	22 (1.9)
Calciumb
Daily does
Under 500 mg	39 3.8)
500-599 mg	92 (8.9)
600-699 mg	257 (24.8)
700-799 mg	20 (1.9)
800-899 mg	8 (0.7)
900-999 mg	1 (0.1)
1000-1199 mg	445 (43.0)
1200-1399 mg	146 (14.1)
1400-1599 mg	6 (0.5)
1600-1799 mg	0 (0)
1800-1999 mg	8 (0.8)
2000 mg or more	14 (1.4)

^aN = 1147 visits where patients were taking vitamin D, and there was information available on the dosage.

^bN = 1036 visits where patients were taking calcium, and there was information available on the dosage.

Of the patients who took calcium at 1 visit or more, 26 different doses of calcium were identified. The most common doses of calcium included 1000 mg (445/1036 visits) and 600 mg (246/1036 visits; Table 3). The median daily dose taken was 1000 mg (Q1-Q3: 600-1000 mg). The lowest dose taken was 100 mg and the highest dose taken was 3800 mg (Table 3).

Vitamin D and Calcium Prescribing and Management Patterns

Twelve (22.6%) sites reported having a comprehensive care pathway or protocol to follow for each patient presenting to hospital with a fragility fracture. Comprehensive pathways, such as Fracture Liaison Services,²⁰ included prescribing/recommending calcium and vitamin D to each patient as well as a plan of referral and/or investigation and patient education. Two of these sites (34 included patients) are Fracture Liaison Services. Twelve (22.6%) sites reported having a noncomprehensive protocol to follow for patients with fragility fracture. These noncomprehensive strategies included only prescribing/recommending calcium and vitamin D or only referring patients with fragility fracture to a specialist or following a protocol inconsistently or on a case-by-case basis. Twenty-nine (54.7%) sites reported that they do not follow a standardized protocol or their fragility fracture management procedure is unknown (Table 4). Vitamin D was prescribed/recommended to 456 fragility fracture patients (456/603, 75.6%) at the postoperative visit, while calcium was prescribed/recommended to 435 fragility fracture patients (435/603, 72.1%) at the postoperative visit (Table 1).

Table 4.

Clinical Site Characteristics.

Characteristic (N = 53 sites)	n (%)
Location
The Netherlands	14 (26.4)
United States	14 (26.4)
Canada	12 (22.6)
United Kingdom	5 (9.4)
Spain	4 (7.5)
Australia	2 (3.8)
Norway	2 (3.8)
Type of hospital
Academic	27 (50.9)
Community/teaching	23 (43.4)
Private clinic	3 (5.7)
Type of funding
Public	39 (72.2)
Private	14 (26.4)
Management of fragility fractures
Comprehensive protocol	12 (22.6)
Noncomprehensive protocol	12 (22.6)
No protocol/unknown	29 (54.7)

Factors Associated With Consistency of Vitamin D and Calcium Supplementation

Compared to nonusers, consistent users of vitamin D were more likely to be from North America (OR: 20.232; 95% CI: 10.894-37.728), to be prescribed or recommended vitamin D postoperatively (OR: 5.938; 95% CI: 3.325-10.605), and to be treated at a site with a management protocol for fragility fractures (OR: 11.117 for comprehensive protocols and OR: 4.054 for noncomprehensive protocols compared to no/unknown protocol). Compared to nonusers, inconsistent users of vitamin D were more likely to be from North America (OR: 17.752; 95% CI: 9.410-33.490), to be prescribed or recommended vitamin D postoperatively (OR: 3.269; 95% CI: 1.844-5.794), and to be treated at a site with a management protocol for fragility fractures (OR: 8.286 for comprehensive protocols and OR: 2.975 for noncomprehensive protocols compared to no/unknown protocol). Age and sex were not associated with consistency of vitamin D use (Table 5).

Table 5.

Factors Associated With Inconsistent Use of Vitamin D and Consistent Use of Vitamin D Versus No Use of Vitamin D.

Vitamin D
Factor	Odds Ratio	95% CI	P Value
Inconsistent users compared to nonusers
Age	0.989	0.962-1.018	.469
Female sex	1.122	0.649-1.941	.679
North America (versus Europe  and Australia)	17.752	9.410-33.490	<.001
Vitamin D prescribed/ recommended postoperatively	3.269	1.844-5.794	<.001
Management/prescribing practices
Comprehensive protocol	8.286	4.633-14.821	<.001
Some protocol	2.975	1.403-6.307	.004
No protocol/unknown	1.000	Ref	Ref
Consistent users compared to nonusers
Age	0.983	0.956-1.010	.201
Female sex	1.653	0.960-2.847	.070
North America (versus Europe  and Australia)	20.232	10.894-37.728	<.001
Vitamin D prescribed/ recommended postoperatively	5.938	3.325-10.605	<.001
Management/prescribing practices
Comprehensive protocol	11.117	6.303-19.606	<.001
Some protocol	4.054	1.996-8.233	<.001
No protocol/unknown	1.000	Ref	Ref

Abbreviation: CI, confidence interval.

We identified a similar trend for calcium use. Compared to nonusers, consistent users of calcium were more likely to be female (OR: 1.815; 95% CI: 1.058-3.114), from North America (OR: 13.156; 95% CI: 7.409-23.361), and to be prescribed or recommended calcium postoperatively (OR: 4.788; 95% CI: 2.775-8.263). Compared to nonusers, inconsistent users of calcium were more likely to be from North America (OR: 13.778; 95% CI: 7.706-24.638), to be prescribed or recommended calcium postoperatively (OR: 2.705; 95% CI: 1.600-4.574), and to be treated at a site with a management protocol for fragility fractures (OR: 8.819 for comprehensive protocols and OR: 3.259 for noncomprehensive protocols compared to no/unknown protocol). Age was not associated with consistency of calcium use (Table 6).

Table 6.

Factors Associated With Inconsistent Use of Calcium and Consistent Use of Calcium Versus No Use of Calcium.

Calcium
Factor	Odds Ratio	95% CI	P Value
Inconsistent users compared to nonusers
Age	0.998	0.971-1.025	.868
Female sex	1.169	0.689-1.986	.562
North America (versus Europe  and Australia)	13.778	7.706-24.638	<.001
Calcium prescribed/ recommended postoperatively	2.705	1.600-4.574	<.001
Management/prescribing practices
Comprehensive protocol	8.819	5.050-15.400	<.001
Some protocol	3.259	1.548-6.859	.002
No protocol/unknown	1.000	Ref	Ref
Consistent users compared to nonusers
Age	0.987	0.961-1.014	.350
Female sex	1.815	1.058-3.114	.030
North America (versus Europe  and Australia)	13.156	7.409 to 23.361	<.001
Calcium prescribed/ recommended postoperatively	4.788	2.775-8.263	<.001
Management/prescribing practices
Comprehensive protocol	9.501	5.482-16.466	<.001
Some protocol	4.385	2.164-8.887	<.001
No protocol/unknown	1.000	Ref	Ref

Abbreviation: CI, confidence interval.

Osteoporosis Medications

Forty-four (7.3%) patients were taking bisphosphonates and 20 (3.3%) patients were taking other medications to treat osteoporosis at baseline. At the first study follow-up visit after surgery, 43 (7.1%) patients were taking bisphosphonates and 14 (2.3%) were taking other medications to manage osteoporosis. Of patients who were taking bisphosphonates or another medication to manage at baseline, approximately half were consistent users of calcium (32/64; 50%) and vitamin D (34/64; 53%).

Discussion

Despite evidence that vitamin D and calcium intake are beneficial for the prevention of refracture in patients who have fragility fractures, our study found that more than one-third of elderly hip fracture patients treated with arthroplasty did not take vitamin D or calcium within the first 12 months after their fracture. An additional one quarter took vitamin D and calcium inconsistently. Patients treated in North America, prescribed calcium and/or vitamin D postoperatively, and who were treated at clinical sites with a comprehensive fragility fracture management protocol were significantly more likely to consistently take calcium and/or vitamin D after hip arthroplasty. Female patients were also more likely to take calcium than males, but not vitamin D. The dosing regimens of both calcium and vitamin D are highly varied, showing a lack of consensus on the optimal dose. A slightly higher proportion of patients taking medications to manage osteoporosis were consistent users compared to patients not on bisphosphonates or osteoporosis medications.

These results are relatively consistent with a recent study on vitamin D supplementation among elderly patients undergoing internal fixation for a hip fracture,¹⁸ although the internal fixation study found a slightly higher rate of consistent vitamin D use (46%) than our study. The similar study in internal fixation of hip fractures¹⁸ also found that patients in North America are more likely to take vitamin D consistently, which is also congruent with our findings. The results of the current study show that there is large variability in dosing regimens of calcium and vitamin D. This is similar to a recent survey of American and Canadian orthopedic surgeons which found that 65% orthopedic surgeons routinely prescribe vitamin D to their fragility fracture patients.¹² In our study, nearly three quarters of patients were prescribed calcium and vitamin D while in hospital, but fewer patients reported taking calcium and vitamin D at study follow-up visits. A 1-year supply of calcium and vitamin D tablets ranges from CAD$20 to CAD$60 depending on brand name and daily dose, making it a very inexpensive medication. This study highlights an issue with compliance of even simple, inexpensive, and widely available medications, which should be taken into consideration when treating elderly orthopedic patients. We also found a very low rate of prescription (10.6% at baseline and 9.5% at the first study follow-up) of bisphosphonates and other osteoporosis medications in this population of fragility fracture patients. It is unknown why the rate of prescription of these medications was so low in this population, but it may point to a gap in care in geriatric orthopedics that should be addressed in future research. There is an opportunity to improve both the rate of prescription/recommendation and supplement adherence to ensure that patients with osteoporosis are getting the care that is needed to manage their osteoporosis and to prevent future fragility fractures.

It should be noted that, for patients who have high dietary calcium intake, supplementation is not required. In fact, it is more desirable for patients to obtain their calcium through diet than through supplementation.^21,22 However, relatively few hip fracture patients have adequate dietary calcium intake and therefore need supplementation. Health Canada reports that elderly men older than 70 years are getting 69% less calcium than the current recommendation and elderly women are getting 63% less calcium than recommended.²³ Clinical practice guidelines, hospital protocols, and educational programs for prevention of fragility fractures should reflect this.

Physicians should monitor patients who are taking vitamin D and/or calcium for possible side effects. Specifically, patients taking high doses of vitamin D should be carefully monitored for falls,^24,25 hypercalcemia, hypercalciuria,²⁶ and gastrointestinal distress.¹⁰ Additionally, patients taking calcium may be at an increased risk of renal calculi, kidney stones, and negative cardiovascular effects, especially if they have cardiovascular, gastrointestinal, and kidney conditions.²⁷

This study is strengthened by the inclusion of a large number of participants from diverse clinical sites in 7 countries. Additionally, the prospective nature of the study allowed us to capture data with little risk of recall bias. Limitations of this study include possible underestimation of the loading doses of vitamin D taken as we did not specifically ask clinical sites to record loading doses. Additionally, clinical sites had to rely on self-reported use of calcium and vitamin D, which may be an overestimate or underestimate of actual calcium and vitamin D intake. We did not ask sites to specify whether the vitamin D was vitamin D₂ or D₃, so that information is unknown. Additionally, we did not record whether patients’ vitamin D levels were being monitored or whether they were referred for any additional management of osteoporosis. Monitoring can have an effect on compliance levels.

Despite well-developed guidelines, a low proportion of elderly hip fracture patients are consistently taking vitamin D and calcium, which may be contributing to poorer bone health and a missed opportunity to reduce the high refracture rate in this cohort. The inconsistency in patient use of calcium and vitamin D found in this study highlights a need for additional high-quality studies to establish a consensus on the ideal dosing regimen for vitamin D and calcium. In addition, patient education strategies along with surgeon educational initiatives and resources are needed to ensure that hip fracture patients receive bone health management beyond fracture care. Our study shows that hip fracture patients, who are the group at highest risk of future hip and other fragility fractures, frequently do not receive sufficient vitamin D and calcium. These patients and their treatment teams should be specifically targeted in future strategies for interventions aimed at fracture prevention.

Appendix A

• Steering Committee: Mohit Bhandari (Chair), P. J. Devereaux, Thomas A. Einhorn, Lehana Thabane, Emil H. Schemitsch, Ken Koval, Frede Frihagen, Rudolph W. Poolman, Kevin Tetsworth, Ernesto Guerra-Farfán, Stephen D. Walter, Gordon H. Guyatt.

• Global Methods Centre: Mohit Bhandari, Sheila Sprague, Kim Madden, Paula McKay, Kerry Tai, Taryn Scott, Marilyn Swinton, Diane Heels-Ansdell, Lisa Buckingham, Aravin Duraikannan (McMaster University).

• US Methods Centre: Thomas A. Einhorn (principal investigator); Heather Silva (research coordination; Boston University Medical Center). Thomas A. Einhorn, Pankajkumar Patel (New York University).

• Netherlands Methods Centre: Ydo V. Kleinlugtenbelt, Ellie B. M. Landman (Deventer Ziekenhuis; Definitive). Martin J. Heetveld, Rudolf W. Poolman, Esther M. M. Van Lieshout, Paul T. P. W. Burgers (Erasmus Medical Centre, Rotterdam; Pilot).

• United Kingdom Methods Centre: Amar Rangan (The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, University of Oxford, University of York), Birgit Hanusch, Lucksy Kottam (The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust).

• Central Adjudication Committee: Mohit Bhandari (Chair), Robert D. Zura, Victoria Avram, Ajay Manjoo, Dale Williams.

• Data Safety Monitoring Board (CIHR): John Antoniou (Chair), Tim Ramsay, Earl R. Bogoch, Andrew Trenholm.

• Data Safety Monitoring Board (NIH): Stephen Lyman (Chair), Madhu Mazumdar, Kevin J. Bozic, Mark Luborsky, Stuart Goodman, Susan Muray, Benjamin K. Potter.

HEALTH Investigators

• The following persons participated as investigators in the HEALTH trial.

Canada

• University of Calgary—Rob Korley, Richard Buckley, Paul Duffy, Shannon Puloski, Eldridge Batuyong, Christopher Martin, James MacKenzie, Jason Werle, Kelly Johnston, Neil White, Marcia Clark, Gregory Abelseth, Stephen Hunt, Justin LeBlanc, Prism Schneider, Kimberly Carcary, Ross McKercher, Lisa Murphy, Melissa Lorenzo.

• University of British Columbia/Fraser Health Authority/Royal Columbian Hospital—Trevor B. Stone, Bertrand Perey, Farhad Moola, Darius Viskontas, Kelly Apostle, Dory Boyer, Robert McCormack, Mauri Zomar, Karyn Moon, Raely Moon.

• St Michael’s Hospital—Aaron Nauth, Emil H. Schemitsch, Michael D. McKee, Jeremy A. Hall, Daniel Whelan, Sarah Ward, David Walmsley, Earl R. Bogoch, James P Waddell, Henry Ahn, Timothy R. Daniels, Milena R. Vicente, Jennifer T. Hidy, Melanie T. MacNevin.

• Sunnybrook Health Sciences Centre—Hans Kreder, David Stephen, Richard Jenkinson, Markku Nousiainen, Terry Axelrod, Veronica Wadey, Sebastian Tomescu, Monica Kunz, Katrine Milner, Melanie MacNevin, Ria De Gorter (Cagaanan), Wesley Ghent, Fathima Adamsahib, Araby Sivananthan, Aimee Theriault, Michelle Arakgi.

• Vancouver General Hospital—Peter J. O’Brien, Piotr A. Blachut, Henry M. Broekhuyse, Pierre Guy, Kelly A. Lefaivre, Dean Malish, Raman Johal, Abdullah Mamun, Irene Leung.

• Hôpital de l’Enfant-Jésus—Luc Bedard, Martin Bédard, Bernard Laliberté, Jean Lamontagne, Pierre Lavallée, Martin Lesieur, François Marquis, Luc Petitclerc, Marie-ève Roger, Stéphane Pelet, Raphaelle Charest-Morin, Alexandre Denault, Hélène Côté.

• Queen Elizabeth II Health Sciences Centre—Chad Coles, Ross Leighton, C. Glen Richardson, Michael Biddulph, Michael Gross, Michael Dunbar, J. David Amirault, David Alexander, Catherine Coady, Mark Glazebrook, David Johnston, William Oxner, Gerald Reardon, Ivan Wong, Kelly Trask, Shelley MacDonald.

• Memorial University of Newfoundland—Andrew Furey, Craig Stone, Keegan Au, William Moores, Minnie Parsons, Valisha Keough, Erin Baker.

• Hôpital du Sacré-Coeur de Montréal—G-Yves Laflamme, Benoit Benoit, Pierre Ranger, Michel Malo, Julio Fernandes, Julie Fournier, Karine Tardif.

• Hôpital Saint-François d’Assise—Etienne Belzile, François Marquis, Norbert Dion, Annie Arteau, Marc Bouchard, Alexandre Leclerc, Michèle Angers, Sylvain Belzile, Sylvie Turmel

• Lakeridge Health—Samir Chhabra, Osama Gharsaa, Abdulmajid Ibrahim, Esmat Dessouki, Omar Dessouki, Aileen Manganaro, Kelly Fusco.

• Ottawa Hospital Research Institute, The Ottawa Hospital—Robert J. Feibel, Hesham Abdelbary, Christopher Kennedy, Paul Kim, Carly St Germain, Johanna Dobransky, Sara A. Ruggiero, Heather Cosgrove.

• Humber River Hospital—Sebastian Rodriguez-Elizalde, Anna Rose Soliman, Sagar Desai, John Townley, Iriss Mariano.

United States

• Lahey Hospital and Medical Center—Andrew Marcantonio, Michael Kain, Lawrence Specht, John Tilzey, John Garfi.

• Mayo Clinic—Andrew Sems, Tab Mabry, Joseph Cass, Michael Torchia, William Cross, Michael Taunton, Joaquin Sanchez-Sotelo, Rafael Sierra, Barbara Foreman.

• Marshall University—Franklin D. Shuler, James Day, Tigran Garabekyan, Felix Cheung, Ali Oliashirazi, Jonathon Salava, Linda Morgan, Timothy Wilson-Byrne, Grant Buchanan, Milad Modarresi, Mary Beth Cordle.

• Indiana University—Brian Mullis, Karl Shively, Andrew Parr, Janos Ertl, Ripley Worman, Mark Webster, Judd Cummings, Valda Frizzell, Molly Moore.

• Orthopaedic Associates of Michigan—Clifford B. Jones, James R. Ringler, Debra L. Sietsema.

• New York University—Thomas A. Einhorn, Kenneth A. Egol, Nirmal C. Tejwani, Roy I. Davidovitch, Ran Schwarzkopf, Jonathan Vigdorchik, James D. Slover, Sanjit R. Konda, Toni Mclaurin, Pankajkumar Patel.

• University Orthopaedic Associates—Carlos Sagebien, David Hardwood, Stephen Kayiaros, Patricia Seuffert.

• Texas Tech University—Enes Kanlic, Amr Abdelgawad, Juan Shunia.

• University of Pennsylvania—Samir Mehta, John L. Esterhai Jr, Jaimo Ahn, Derek Donegan, Atul Kamath, Neil Sheth, Annamarie Horan, Patrick Hesketh, Thomas Rose.

• The CORE Institute—Clifford B. Jones, Jason A. Lowe, Russell Meldrum, Samir Ahmed, Debra L. Sietsema.

• Duke University Medical Center—Rachel Reilly, Robert D. Zura, Steven Olson, Maria Manson, Cameron Howes.

• University of Mississippi Medical Center—Benjamin M. Stronach, Patrick F. Bergin, Jennifer S. Barr, Clay A. Spitler, Josie Hydrick, Leslie N. Johnson.

• Boston University Medical Center—Thomas A. Einhorn, Paul Tornetta III, William R. Creevy, Heather Silva, Michelle J. Lespasio, Hope Carlisle.

• Colorado Orthopedic Consultants—Craig Davis, Philip Stull, Stewart Weinerman, Peter Weingarten, Steven Lindenbaum, Michael Hewitt, Rebecca Danielwicz, Janell Baker,

• Mission Hospital Research Institute—Charles DePaolo, Christina Riggsbee.

• Park Nicollet Institute—Gregg Strathy, Kathleen Peter, Paul Johnson, and Meaghan Morton,

• Rothman Institute—Javad Parvizi, Tiffany Morrison.

• Rubin Institute for Advanced Orthopaedics—Michael Mont, Donald E. Delanois, Bhaveen Kapadia, Kimona Issa, and Marylou Mullen.

• SUNY Buffalo—Mark Anders, Christopher Mutty, Matthew Phillips, Sridhar Rachala, Mary Bayers-Thering.

• Allegheny—Timothy J. Sauber, Edward Westrick, Joseph Guth, Michael H. Maher.

• St Elizabeth Health Center—Tyson T. Schrickel, John V. Gentile, Barbara M. Hileman, Elisha A. Chance.

• University of California Irvine—David Zamorano, John A Scolaro, Douglas Kiester, Deeba Pourmand.

• University of Utah—Erik N. Kubiak, Jeremy Gililland, David Rothberg, Christopher Peters, Christopher Pelt, Ami R. Stuart, Kirby Corbey, Andrea Gurule.

• Emory University School of Medicine—James Roberson, Thomas Bradbury, Greg Erens, Kyle Webb.

• University of Arizona—Michael Dohm, Cindy Fastje, José Luis Camarena, Maria Gordon.

The Netherlands

• Deventer Ziekenhuis—Ydo V. Kleinlugtenbelt, Hans-Peter W. van Jonbergen, Willem H. Roerdink, Joost M. Reuver, Alexander F. W. Barnaart, Elvira R. Flikweert, Daniela D. Langeloo, Rinco C. T. Koorevaar, Hannie H. F. Elskamp-Meijerman, Ellie B. M. Landman.

• Amphia Ziekenhuis—Leon H. G. J. Elmans, Joost A. A. M. van den Hout, Adrianus J. P. Joosten, Ad F. A. van Beurden, Stefan B. T. Bolder, Denise Eygendaal, Adrianus F. C. M. Moonen, Rutger C. I. van Geenen, Eric A. Hoebink, Robert Wagenmakers, Wouter van Helden.

• Tergooiziekenhuizen—Harm M. van der Vis, Lijkele Beimers, Jasper de Vries, Arthur W. Zurcher, G. H. Rob Albers, Maarten Rademakers, Stefan Breugem, Ibo van der Haven, Pieter Jan Damen, Gythe H. Bulstra, Martin M. Campo, Mathijs P. Somford, Daniël Haverkamp.

• Gelre Ziekenhuizen—Hugo W. Bolhuis, Pieter H. J. Bullens, Mike Hogervorst, Karin E. de Kroon, Rob H. Jansen, Ferry Steenstra, Eric E. J. Raven.

• Spaarne Ziekenhuis—Peter A. Nolte, Michel P. J. van den Bekerom, Tjitte de Jong, Arthur van Noort, Diederik A. Vergroesen, Bernard G. Schutte.

• Diaconessenhuis Leiden—Rover Krips, J. Bernard Mullers, Hans Schüller.

• Medisch Centrum Haaglanden—Stefan B. Keizer, Jan-Willem A. Swen, Peter H. C. den Hollander, Bregje J. W. Thomassen.

• IJsselland Ziekenhuis—W. Peter J. Fontijne, Saskia C. Wiersma, Bastiaan Boetes, Edgar J. T. ten Holder.

• Onze Lieve Vrouwe Gasthuis (OLVG)—Rudolf W. Poolman, Bauke W. Kooistra, Willem Jan Kleyn Molekamp, Frank R. A. J. de Meulemeester, Arthur E. B. Kleipool, Robert Haverlag, Maarten P. Simons, Eduard L. A. R. Mutsaerts, Diederik H. R. Kempen, Mark C. Altena, Dirk Jan F. Moojen, John (S.J.) Ham, Arnard van der Zwan, Derek F. P. van Deurzen, Michel P. J. van den Bekerom, Vanessa A. B. Scholtes, Mariëlla E. M. Volkers, Amanda D. Klaassen, Loes W. A. H. van Beers, Nienke W. Willigenburg.

• Isala Clinic—Sven H. van Helden, R. G. Zuurmond, Adriaan Mostert, P. Houben, G. Solinge, W. R. Spanjersberg, R. Nijveldt, K. van Egmond, Lonneke Buitenhuis.

• Ruwaard van Putten Ziekenhuis—Rob Kooijman, Roelf R. Postema, René J. T. M. Bleker, Harald I. H. Lampe.

• Slotervaartziekenhuis—Lein Schuman, John Cheung, Frank van Bommel, W. Paul C. A. Winia, Daniel Haverkamp, Harm van der Vis.

• Leids Universitair Medisch Centrum—Huub J. L. van der Heide, Jochem Nagels, Enrike H. M. J. van der Linden-van der Zwaag.

• Gelderse Vallei—Jan P. van Dijk, Wouter H. van Helden.

• Flevoziekenhuis—Mark L. M. Falke, Frans J. Kurek, Adrianus C. H. Slingerland.

• St Antonius Ziekenhuis—Remmelt Veen, Bauke Kooistra, Nienke Wolterbeek.

Spain

• Hospital Vall d’Hebrón—Ernesto Guerra Farfan, Jordi Teixidor Serra, Jordi Tomás Hernández, Vicente Molero García, Jordi Selga Marsà, Juan Antonio Porcel Vázquez, Joan Minguell Moñart, Maria Villar Casares, Jaume Mestre Torres, Sandra Ponce Ruiz, Teresa Sanclemente Boli, Judith Sánchez-Raya, Míriam Garrido Clua.

• Hospital Universitari Mútua de Terrassa—Pablo Castillón, Francesc Anglés, Josep Torrent, Bárbara Lozano, Ibón López, Josep Lluis Cabré, Inma Puig de la Bellacasa, Agustí Bartra, Natalia Ibañez, Emili Cañete, Iban Clares, Martí Carles Bernaus.

• Hospital Dr Josep Trueta—Miguel Angel Froufe, Lluis Marull Serra, Samer Al-dirra, Salvador Geli, Diana Noriego, Anna Vaño, Maria Jose Martinez, Didac Masvidal, Cristina Martinez Merchan.

• Hospital Universitario Costa del Sol—Enrique Guerado, Encarnación Cruz Ocaña, Juan Ramon Cano, Ana Cervan, Manuel Vides, Julio Rodriguez, Miguel Rodriguez Solera, Manuel Godino, Miguel Hirschfeld, Laura Ramos, Antonio Royo, Adolfo Galán, Paqui Fontalba, Pilar Gavira

• University Hospital 12 de Octubre—Jose Moreno Beamud, Rafael Navarro Arribas, Emilio Delgado, Arantxa Capel.

• Hospital Clinic de Barcelona—Oscar Ares, Jenaro Fernandez-Valencia, Alonso Zumbado, Marta Gutiérrez Gándara.

Norway

• Oslo University Hospital—Frede Frihagen, Lars Nordsletten, John Clarke-Jenssen, Geir Hjorthaug, Kaare Midtgaard, Lene B. Solberg, Carl Erik Alm, Jonas Rydinge, Marianne Westberg, Ole Christian Brun, Ida Hveem, Elise Berg Vesterhus, Anne Christine Brekke, Sissel Knuts.

• Ringerike Sykehus Hospital—Ingunn Skaugrud, Engelke Randers.

United Kingdom

• Royal Cornwall Hospital—Manish Divekar, Pallakkad Easwaran, Daniel Williams, Robin Kincaid, Shaun Sexton, Shyam Maimen, Rory Middleton, Gavin Bartlett, Fiona Hammonds, Benita Adams, Anna Fouracres, Jackie Dingle, Jessica Summers, Nicki Devooght-Johnson, Alyson Andrew, Abigail Weeks.

• East Sussex Healthcare—Adrian Butler-Manuel, Oliver Keast-Butler, Guy Selmon, Andrew Armitage, Simon Pearce, Simon Hoskinson, Miranda Champion, Satish Ganesan, Manjunathan Sivaprakasam, Zaid Al-Wattar, Paul Cameron, Kate Weatherly, Kim Miles.

• Leicester Royal Infirmary—John Davison, Jonathon White, Andrew Brown, S. Subramanian, Jenny Nichols, Aujlia Randeep, Christina Haines, Manjit Attwal, Debbie Lee, Mona Mohamed, Sharon Siddons.

• University Hospital of North Tees—Rajesh Nanda, Christopher Tullock, Rajnikanth Logishetty, Antoni Nargol, Richard Jeavons, Angela Bradbury, Carol Bowler, Janet Austin.

• Northumbria Healthcare—Dominic Inman, Mike Reed, Ajay Malviya, An Murty, Paul Partington, Ian Carluke, Derek Kramer, Kevin Emmerson, Scott Muller, David Townshend, Juhu Joseph, Jonathon Coorsh, Sameer Khan, Rajesh Kakwani, Helen Shirley, Kerry Third, Christine Dobb.

• Barts Health NHS Trust—Joshua Lee, Steve Millington, Stephen Key, Daud Chou, Alex Vris, Sammy Hanna, Anna Berridge, Jamila Kassam, Catherine Hilton, Shanaz Ahmad.

• Cambridge University Hospital—Christopher Gooding, Wasim Khan, Stephen McDonnell, Peter Hull, Joseph Queally, Alastair Vince, Dennis Edwards, Frances New, Simone Hargreaves, Debbie Read.

• The James Cook University Hospital—Birgit Hanusch, Amar Rangan, Paul Baker, Anthony Hui, Craig White, Ian Wallace, Simon Jameson, James Webb, William Eardley, Lucksy Kottam, Alanna Milne.

• Yeovil District Hospital—Matthew Hall, Roshan Raghavan, Benedict Lankester, Paul Latimer, Paul Porter, Istvan Batta, Alison Lewis, Lucy Pippard.

• South Devon Healthcare—Gordon Higgins, Veronica Conboy, Yousef El-Houdiri, Steve Blake, David Isaac, Pauline Mercer.

• Sherwood Forest Hospital—Sreebala Srinivasan, Sachin Badhe, Amit Bidwai, Rebecca Boulton, Sarah Shelton.

Australia

• University Hospital Geelong, Deakin University—Richard Page, Andrew Thomson, Simon Williams, Chatar Goyal, David Bainbridge, Richard Angliss, Ben Miller, Graeme Brown, Kevin Eng, David Bowyer, John Skelley, Glenn Boyce, Adam Watson, Nathan Donovan, Amanda Cowland, Sally Beattie.

• The Alfred—Susan Liew, Harvinder Bedi, Ashley Carr, Andrew Chia, Steve Csongvay, Craig Donohue, Stephen Doig, Elton Edwards, Max Esser, Richard Freeman, Andrew Gong, Doug Li, Russell Miller, Lu Ton, Otis Wang, Ian Young, Ash Moaveni, Matthias Russ, Siva Chandrasekaran, Arvind Jain, Adam Dowrick, Zoe Murdoch, Claire Sage.

• Prince Charles Hospital—Catherine McDougall, Sue Grice, Scott Crawford, Dinesh Sharma, Andrew Patten, Sam Young, Rebecca Ferrier.

Finland

• Turku University Hospital—Matti Seppänen, Mika Junnila, Jari Mokka, Kari Isotalo, Niko Strandberg, Jani Knifsund, Keijo Mäkelä, Keemu Hannes, Mikko Karvonen, Stefan Suvitte, Saara Meronen.

New Zealand

• North Shore Hospital—Marla Ross, Anand Segar, Otis Shirley, Francis Ting, Rob Sharp, Luke Brunton, John Mutu-Grigg, Sherina Holland.

South Africa

• University of KwaZulu-Natal/Grey’s Hospital—Rian Smit, Leonard Marais, Reitze Rodseth, Simphiwe Gumede.