Improving Mobility and Reducing Disability in Older People Through Early High-Dose Vitamin D Replacement Following Hip Fracture: A Protocol for a Randomized Controlled Trial and Economic Evaluation

Abstract

Hypovitaminosis D is particularly common among older people with a proximal femoral (hip) fracture and has been linked with poorer lower extremity functioning, falls, and fractures. There is evidence that disability severity and fall rates may be reduced by adequate vitamin D replacement. However, the ideal regimen for vitamin D administration to have these benefits in older people who have been in the hospital has not been established. This randomized controlled trial will investigate the effects of an oral vitamin D loading dose with maintenance oral vitamin D and calcium on lower extremity function (gait velocity), correction of hypovitaminosis D, falls, and fractures among older people after hip fracture surgery. The cost-effectiveness of the REVITAHIP program from the health and community service provider’s perspective will also be established, as will predictors of adherence with the treatment. A total of 450 older people who have recently had a hip fracture requiring surgical intervention will be screened to achieve 250 participants for the study. Participants will have no medical contraindications to vitamin D replacement. The primary outcome measure will be mobility-related disability as measured with the 2.4-m gait velocity test. Secondary measures will be 25-hydroxyvitamin D (25-OHD) levels at 2, 4, and 26 weeks, number of falls and fractures, and additional measures of mobility, disability, quality of life, health system and community–service contact, adherence to the intervention, and adverse events. After surgical fixation and being deemed medically stable, participants will be randomly allocated to an intervention or placebo-control group. Participants of the intervention group will receive initial oral 250 000 IU (5 × 50 000 IU) vitamin D3 tablets. Both groups will receive oral maintenance vitamin D3 and calcium and will follow the usual hip fracture rehabilitation pathway. The study will determine the impact of a vitamin D loading dose on mobility-related disability in older people following hip fracture and will discuss the efficacy and cost-effectiveness of a loading dose vitamin D replacement more generally. The results will have direct implications for future use of vitamin D therapy for this high-risk group.

Background

Hip fractures are a major public health issue for older people. Despite the age-specific incidence of osteoporotic hip fracture in Australia, and some other countries, decreasing over the plast 10 years, the actual numbers of hip fractures are increasing steadily because of the increasing proportion of older people in the population.¹ Outcomes for people surviving hip fracture are poor, with the majority of patients not recovering their previous level of function. For example, it has been established that 50% of people surviving a hip fracture require long-term help with routine activities and cannot walk unaided, and 25% require full-time nursing-home care.² As most people do not recover fully from a hip fracture, personal and societal costs are often incurred following hip fracture surgery because of the need for rehabilitation, outpatient visits for follow-up treatment, temporary residential aged care facility placement if required, and assistance with activities of daily living at home during the recovery period.¹ Improving functional parameters following a hip fracture has the potential to be of great benefit to older people by reducing disability and enhancing quality of life and could also reduce direct treatment costs and costs of long-term community or residential aged care services. Mobility is the key activity underlying functioning and quality of life.

Hypovitaminosis D is commonly associated with hip fracture in older people^3,4 and occurs because of multiple factors such as decreased sun exposure with reduced skin production of vitamin D and low dietary D2/D3 intake. Vitamin D replacement has been used successfully to reduce such fractures, as well as falls among older people.^5–7 However, in the absence of preventive treatment, hypovitaminosis D following hip fracture may result in proximal muscle weakness, pain, reduced dynamic balance and performance speed,⁸ affecting mobilization during the acute postoperative and rehabilitation periods.

Our research group has conducted a pilot study examining the efficacy and effectiveness of moderate-dose oral vitamin D therapy in maintaining 25-hydroxyvitamin D (25-OHD) levels following a hip fracture. We reported the novel finding that 25-OHD levels can decrease significantly after hip fracture in the postacute period (14 days) despite standard oral vitamin D treatment (37.5% on 1000 IU vitamin D reduced 25-OHD levels).⁹ Although 1000 IU of vitamin D is suitable for maintenance, this dose raises 25-OHD levels by only around 13 nmol/L and takes a relatively long time to do so.¹⁰ Further, the occurrence of hypovitaminosis D can exacerbate symptomatic hypocalcemia which may occur with intravenous bisphosphonate (zoledronic acid), a first-line recommended treatment following hip fracture.¹¹ The result may be life threatening and require hospitalization to prevent additional morbidity and mortality risk.¹² Therefore, ensuring that 25-OHD levels in older people are replenished in a timely fashion may reduce the likelihood of osteoporosis by providing a more optimal environment for bisphosphonates to act on the bone matrix, while simultaneously influencing nonskeletal factors, such as muscle function and pain, by reversing the deleterious effects hypovitaminosis D has on osteomalacia.¹³ Improving both skeletal and nonskeletal factors with vitamin D replacement has potential to improve postacute and rehabilitation status in terms of mobility and functional parameters, as well as to prevent falls and further fractures in the medium and long term.

To date, however, there are no current proven strategies in effective replenishment of vitamin D after hip fracture surgery and little evidence that mobility-related disability and/or falls can be minimized in older people following a hip fracture. Several recent studies have examined the impact of an initial loading dose of vitamin D followed by daily oral maintenance vitamin D and calcium formulations in the 12-month period after a hip fracture, reporting improvements in 25-OHD levels,¹³ prevention of symptomatic hypocalcemia,¹⁴ and reduced risk of further hip fracture,¹⁵ with no indication of adverse effects of a single high-dose vitamin D.^10,15,16 One recent study in which otherwise well women from the general community received a single annual dose of vitamin D (500 000 IU or placebo) with no maintenance dose, reported an increase in falls and fractures, tending to occur 1 to 3 months after the large oral dose.¹⁷ No good explanation for these findings was proposed either by the authors or in an accompanying editorial.¹⁸ No studies have examined the influence of such a loading dose on mobility-related disability following hip fracture.³⁰

The present randomized controlled trial seeks to build on previous pilot work by evaluating the effect of an initial loading dose of vitamin D to improve rehabilitation outcomes following hip fractures. The study will examine the impact of a loading dose of vitamin D on physical performance measures designed to measure mobility-related disability. Physical performance measures, such as gait speed over a defined distance, have been shown to be valuable in predicting future health and functioning in populations of older adults.^19,29 The study hypotheses are (1) the supply of an oral loading dose vitamin D reduces mobility-related disability as measured by improved gait velocity and increases 25-OHD levels when compared with control group; (2) improved physical performance resulting from the loading dose vitamin D will lead to improved quality of life and reduced likelihood of falls and fractures when compared with control group; (3) the intervention is cost effective from the perspective of health and community services. The study will also examine adherence to osteoporosis therapies, a major issue in public health research and clinical practice²⁰ and will identify predictors of adherence to a combined calcium–vitamin D therapy in the posthospital population.

Methods and Design

Design

A randomized controlled trial will be conducted among approximately 450 participants recently admitted to the hospital. Figure 1 gives an overview of the study design.

Figure 1.

Flow of participants through the REVITAHIP trial.

Participants

Participants who fulfill the following general inclusion criteria admitted to 1 of 5 participating public hospital wards in Sydney, Australia, will be invited to participate:

1. Adults (aged 65 years or over) presenting with a hip fracture requiring surgical treatment.

2. Able to provide informed consent, either directly or via the “person responsible.”

3. Willingness to participate in and comply with the study.

4. Deemed suitable by the treating medical team.

5. Able to take loading dose vitamin D within 7 days after operation.

People will be ineligible to participate in the trial if they:

1. are unable to read, speak, or write English language;

2. are bed bound prior to fracture, or life expectancy deemed less than 1 month by the treating clinical staff;

3. have hypercalcemia (serum calcium >2.65 mmol/L);

4. have a history of renal stones;

5. have thyrotoxicosis;

6. have Paget disease;

7. have malignancy (except skin cancer) and associated pathological fractures;

8. have significant renal impairment (serum creatinine >0.15 mmol/L);

9. have liver disease (alanine aminotransferase or aspartate aminotransferase level >2 times the upper limit of the normal range);

10. are undergoing treatment with calcitriol; and

11. are undergoing treatment with >=1000 IU daily oral vitamin D3, or

12. have known sarcoidosis......

The Northern Sydney Central Coast Area Health Service (NSCCAHS) Harbour Human Research Ethics Committee (HREC) approved the study protocol (HREC Number 10/HARBR/14) on May 13, 2010.

Randomization

After consent and completion of the baseline assessment, participants will be formally entered into the study and randomized to intervention or control groups. Randomization will occur using a computer-generated random number schedule with variable block sizes of 2 to 6. It will be performed centrally by an investigator not involved in recruitment or assessments. To conceal allocation, study staff will ring a central telephone number to be notified to which group the participant has been randomized.

Intervention

Patients in the treatment group will receive a loading dose of oral vitamin D3 (5 tablets of 50 000 IU, Calciforte Strong [API Pharmaceuticals, New Zealand], total 250 000 IU), ideally within 96 hours but up to 7 days postsurgery.

Patients in the control group will receive 5 placebo tablets identical in appearance to the active tablets, ideally within 96 hours but up to 7 days postsurgery.

Both groups will be provided with a twice daily oral calcium–vitamin D combination tablet (calcium 500 mg and vitamin D3 400 IU; Calcia, Nycomed Pharmaceuticals: 2 Lyonpark Road, North Ryde NSW 2113). Participants unable to tolerate the oral tablet formulations will be switched to a daily oral sachet of calcium–vitamin D combination effervescent granules (calcium 1000 mg and vitamin D3 880 IU; Calvid, Pharmaceutical Special Products: 2 Albert Road, Moonah, Tasmania. Australia 7009).

Those patients in either group with severe hypovitaminosis D (25OHD <10 nmol/L) will be commenced on an oral moderate-dose vitamin D of 2000 units twice a day for 14 days to ensure adequate and timely replacement. There is some evidence that this latter approach can effectively improve 25-OHD levels in the postacute period.⁹

Outcomes

Data Collection Processes

All participants will undergo 5 assessments. The baseline assessment will be conducted in the inpatient setting at the time of randomization and administration of the loading dose vitamin D. Further assessments will consist of 3 face-to-face interviews at week 2, 4, and 26 and 1 telephone assessment at week 12, after baseline assessment. Assessments will be conducted by research assistants (physiotherapists or nurses) based at each hospital. Each assessment will take about 30 minutes to complete. All assessors will be unaware of the group allocation of participants.

Data will be collected from medical records, self-report questionnaires and calendars, and physical assessments. Information on medical history, diagnoses, and medication will be collected from medical records at baseline assessment. At the baseline assessment, all participants will receive a personalized 6-month calendar on which to record falls and use of health and community services. These calendars will be reviewed during scheduled assessments. Participants will also be asked to complete a quality-of-life questionnaire (EQ5D) at baseline, week 12 and 26. Participants who report falling will be asked during interviews to provide information about the circumstances and consequences of the fall. Staff conducting follow-up phone interviews and entering data will be unaware of the participants' group allocation.

Primary Outcome Measure

Gait velocity over 2.4 and 6 m will be measured at baseline, week 2, 4, and 26 and will be the primary outcome measure in this trial. Gait velocity will be measured with or without a walking aid. If a participant requires direct assistance from another person for mobility, this will be scored as a velocity of 0 m/sec. Objective measures of lower-extremity function (such as gait velocity) have been found to be highly predictive of subsequent disability^21,22 and mortality.²³ Gait velocity can be reliably recorded (ICC .79), is responsive, is predictive of overall functioning²⁴ and is associated with survival in older adults.²⁹

Secondary Outcome Measures

Secondary outcome measures will be the number of falls, fractures and hospitalizations, activities of daily living (using the Barthel Index²⁵), quality of life (EQ5D²⁶), 25-OHD and calcium levels, grip strength, health system and community service utilization, adherence to calcium and vitamin D supplements (expressed as a percentage of the initial dose and as a percentage of subsequent doses), and adverse events (including cardiovascular events and death). Adverse events will be examined by an independent group of clinicians who will conduct a 6 monthly review and adjudicate on these. The secondary measures provide additional depth to understand the effects of a high loading dose of vitamin D and to enhance economic analyses. The relationship between these additional measures and gait velocity will also be assessed. These secondary outcome measures are described in more detail below.

Falls will be recorded monthly using the calendars where participants live in the community, or using residential aged care facility or hospital records where participants are in care. A fall will be defined according to the Kellogg definition²⁷ as an incident in which the body unintentionally comes to rest on the ground or other lower level which is not as a result of a violent blow, loss of consciousness, and sudden onset of paralysis as in a stroke or an epileptic seizure. Where a fall is recorded, determination according to this definition will follow via interview with the patient or their carer.

Fractures and hospitalizations will also be recorded by the participants if living in the community or confirmed by care facility records and will be verified by contact with the participant’s general practitioner or hospital.

Quality of life will be assessed using the EQ5D (Euroqol), a valid and reliable measure of quality of life in older people.²⁶

25-OH dihydroxyvitamin D levels will be determined using the DiaSorin assay and will be measured at baseline, 2-, 4-, and 26-week visits.

Grip strength in kilograms will be assessed using a portable dynamometer (JAMAR hydraulic Hand Dynamometer manufactured by Sammons Prestons: Access Health. Unit 1 Rear, 194-196 Whitehorse Rd, BLACKBURN VIC 3130 Australia).

Health and community service contact will be recorded by participants if living in the community or confirmed by care facility records and followed up by interviewers at 4, 12, and 26 weeks.

Calcium/vitamin D adherence rates will be recorded by participants or their carer if living in the community or confirmed by care facility records. Measurement of adherence by self-report is the most common method of assessing adherence.²⁸ Self-reporting may overestimate adherence but careful and nonjudgmental questioning during interview is likely to elicit the true level of adherence.²⁰ Adherence will be assessed at week 2, 4, and 26. Actual participant adherence at each visit will be recorded (as the number of tablets at the visit).

Adverse effects will be assessed during interviews at week 2, 4, 12, and 26 by asking open-ended questions about treatment complications. Participants will be advised to inform study staff immediately if they experience any major adverse effects (lasting for more than 48 hours and interfering with daily activities or requiring medical attention).

Statistical Analysis

Data will be coded to permit blinding to group allocation in the statistical analysis. Differences in the primary outcome measure between the 2 groups will be analyzed using Student t test based on change scores. Separate analyses will be performed on week 2, 4, 12, and 26 follow-up data, as well as analyses to assess changes over time within groups. Similar methods will be used for secondary outcomes where data are continuous and will use the continuity corrected χ² test where outcome measures are categorical. Predictors of changes in gait velocity and adherence will be examined using multiple linear regression models and analysis will be by “intention to treat.”

Economic Analysis

Data will be collected regarding costs of vitamin D supplements (including estimated staff and material costs) and estimates for inpatient hospital admissions, emergency department presentations, and other health and community service contacts (from the monthly calendars). Incremental cost-effectiveness ratios will be calculated in terms of (a) the incremental cost per fall prevented, and (b) the incremental cost per quality-adjusted life year (QALY) gained in the treatment group compared with the control group. Best-case and worst-case scenarios will be determined. Bootstrapping will be used to estimate a distribution around costs and health outcomes and to estimate the confidence intervals around the incremental cost-effectiveness ratio. One-way sensitivity analysis will be conducted around key variables, and a probabilistic sensitivity analysis will be conducted to estimate the joint uncertainty in all parameters; a cost-effectiveness acceptability curve (CEAC) will be plotted. A CEAC provides information about the probability that an intervention is cost effective, given a decision maker’s willingness to pay for each additional QALY.

Sample Size Calculation

Calculations are based on statistical power of 80% with the α set at .05 (2-sided test). To address the primary hypothesis of the study, an estimated sample size of 125 per group is required to show a 10% difference in mean gait velocity improvement at the 4-week follow-up. Over 12 months and 5 hospital sites, we would expect at least 450 patients to meet eligibility criteria and to present for consent. It is estimated that (1) 25% of people will decline to enter the study (or the person responsible would not be contactable in the time required); (2) about 10% of people will die over the 6-month follow-up; (3) a further 5% to 10% will be lost to follow-up. Thus, approximately 246 of 450 patients would remain—enough to satisfy the requirements of the primary outcome measure. Differences between groups on other variables of interest will be assessed within this sample-size framework.

Discussion

The results of this trial will be the first to provide potential mobility and functional prognostic data in a randomized controlled multicenter study. The strategy to be examined is readily transferable to routine clinical practice and is applicable throughout Australia. The results will enable health professionals to adopt an evidence-based approach to administer vitamin D following hip fracture. In addition, the results should also guide decisions about the value of providing subsidies to reduce or eliminate cost for the oral maintenance vitamin D/calcium supplementation.

This trial tests a simple and readily applied health technology that is applicable to large numbers of people with hip fractures. We expect that the results of this study overall will indicate whether it is feasible to achieve sufficient vitamin levvels in the postacute period following hip fracture surgery to reduce mobility-related disability (as measured by increased gait velocity), with corresponding reduction in the incidence of falls and additional hip and other fractures. The results will also clarify the importance of monetary cost of supplementation as a factor influencing adherence with their use. If effective, the high-dose vitamin D treatment will be incorporated into standard hip fracture treatment protocols.