Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing

Vitamin D supplements are increasingly being recommended to healthy adult fracture patients
without an osteoporotic injury. Although this is a relatively new practice pattern, the basis
for this adjunct therapy is grounded in the high hypovitaminosis D prevalence rates (up to
75%) among healthy adult fracture patients, and the strong biologic rationale for the role of
vitamin D in fracture healing. Briefly, experimental animal studies have demonstrated that
the concentration of vitamin D metabolites is higher at a fracture callus compared to the
uninjured contralateral bone, vitamin D supplementation leads to decreased time to union and
increased callus vascularity, and increases mechanical bone strength compared to controls.
While evidence to confirm that vitamin D supplementation improves fracture healing in
clinical studies does not exist, the pre-clinical data are compelling and worthy of further
investigation.

With modern orthopaedic surgical care, rates of complications following tibia and femoral
shaft fractures can be as high as 15%. Complications, including delayed union, nonunion, or
infection often require secondary surgical procedures and result in profound personal and
societal economic costs. While surgeons continue to seek advances in surgical technique, it
is becoming increasingly obvious that innovations in orthopaedic techniques or implants are
unlikely to eliminate complications. As a result, considerable attention is currently focused
on adjunct biologic therapies, such as vitamin D.

A recent survey of 397 orthopaedic surgeons showed that only 26% routinely prescribe vitamin
D supplementation to adult fracture patients. Of the 93 surgeons who indicated that they
routinely prescribe vitamin D supplementation, 29 different dosing regimens were described
ranging from low daily doses of 400 IU to loading doses of 600,000 IU. This suggests a high
level of clinical uncertainty surrounding the use and optimal dose of vitamin D
supplementation in adult fracture patients. If vitamin D supplementation improves fracture
healing outcomes, then there is a large opportunity to increase its use; however, before
widespread adoption occurs, research is needed to optimize the dosing strategy, establish the
dosing safety in the immobilized fracture healing population, and overcome potential
medication adherence issues among the often marginalized patients that suffer trauma.

The long-term goal of our research program is to conduct a large phase III RCT to determine
which dose of vitamin D3 supplementation optimally improves acute fracture healing outcomes
in healthy adult patients (18-50 years). The current proposed phase II exploratory trial will
perform important preliminary work to test the central hypothesis that vitamin D3 dose and
timing of administration is critical for improving fracture healing at 3 months. This trial
will also inform the feasibility of the large phase III RCT.

Inclusion Criteria:

1. Adult men or women ages 18-50 years

2. Closed or low grade open (Gustilo type I or II) tibial or femoral shaft fracture

3. Fracture treated with a reamed, locked, intramedullary nail

4. Acute fracture (enrolled within 7 days of injury)

5. Provision of informed consent.

Exclusion Criteria:

1. Osteoporosis

2. Stress fractures

3. Elevated serum calcium (>10.5 mg/dL)

4. Atypical femur fractures as defined by American Society for Bone and Mineral Research
(ASBMR) criteria

5. Pathological fractures secondary to neoplasm or other bone lesion

6. Patients with known or likely undiagnosed disorders of bone metabolism such as Paget's
disease, osteomalacia, osteopetrosis, osteogenesis imperfecta etc.

7. Patients with hyperhomocysteinemia

8. Patients with an allergy to vitamin D or another contraindication to being prescribed
vitamin D

9. Patients currently taking an over the counter multivitamin that contains vitamin D and
are unable or unwilling to discontinue its use for this study

10. Patients who will likely have problems, in the judgment of the investigators, with
maintaining follow-up

11. Pregnancy

12. Patients who are incarcerated

13. Patients who are not expected to survive their injuries

14. Other lower extremity injuries that prevent bilateral full weight-bearing by 6 weeks
post-fracture.