SOUTHAMPTON, UK—A randomized, placebo-controlled trial meant to confirm open-label data indicating that a single yearly intramuscular (IM) injection of vitamin D2 could reduce fracture risk in elderly persons instead found that the treatment had no protective effect and in fact was associated with a slightly increased risk of hip fracture in some patient groups. The trial, reported by Helen Smith, MD, from the department of primary care, Cyrus Coper, DM, FRCP, professor of rheumatology at the University of Southampton, UK, and colleagues was published early online in Rheumatology.¹

Other experts have pointed out that the patients in this study had relatively high baseline vitamin D levels and that the treatment protocol used vitamin D2 (ergocalciferol) rather than the perhaps more potent vitamin D3 (cholecalciferol).

In an accompanying editorial, R. M. Francis, MD, with the musculoskeletal research group at the University of Newcastle-upon-Tyne in the UK wrote, "Given the paradox of the high prevalence of vitamin D insufficiency and yet the apparent lack of consistent benefit of vitamin D supplementation in fracture prevention, future studies of supplementation should include more extensive measurement of serum 25-OHD (serum 25-hydroxyvitamin D) and PTH (parathyroid hormone)."

Relatively healthy patients, one yearly shot of vitamin D2

The randomized, double-blind, placebo-controlled trial included upwards of 9000 patients over age 75. More than 87% of patients were still living in their own homes, and slightly more than one third had a history of previous fracture. Median age was 79.1. The primary endpoint was all nonvertebral fractures. The study was conducted to detect a 30% difference in fracture rate. Subjects were randomized to once-year IM injections of 3000,000 IU ergocalciferol or placebo each year for 3 years. Yearly IM injection is preferable because it might circumvent the adherence problems associated with long-term oral vitamin D supplementation. New fractures were detected using postal questionnaires every 6 months and corroborated at the annual visits to the practice nurse as well as by hospital and general practice records.

In the group as a whole, intention-to-treat analysis showed no difference in fracture rates over the 3-year period. "There was no evidence for a protective effect of vitamin D against fracture at any site," Dr. Smith reported. In fact, there was "a small, but statistically significant (P = .04) excess risk of hip fracture associated with allocation to treatment with vitamin D," particularly among women. Vitamin D2 supplementation also had no effect on the incidence of falls in this population.

Levels of 25-OHD, PTH , and 1,25-dihydroxyvitamin D (1,25-DHD) were measured in a subgroup of 43 patients. Mean plasma 25-OHD at baseline was 56.5 ng/mL, and this increased a nonsignificant 21% in the actively treated patients at 4 months; this resulted in a similarly nonsignificant 17% suppression of PTH.

"Although too small to allow detailed inference, this subset clearly demonstrated that our subjects were relatively vitamin D replete, with only around 25% falling into the range of modest or severe deficiency (<30 ng/mL).... [T]he available data suggest that this intervention was ineffective in reducing fractures in a relatively vitamin D replete population," the authors conclude.

D3 better than D2?

Subsequent to the design of this trial, the researchers became aware that vitamin D2 "has an attenuated effect when compared with vitamin D3." Dr. Francis pointed out that a study in normal healthy men had shown that vitamins D2 and D3 as oral supplements produced similar increases in serum 25-OHD over the first 3 days after treatment but that levels soon fell slightly below baseline in the men treated with vitamin D2.

Translating research into practice

"It is difficult to interpret [the results of this study]," vitamin D expert Michael F. Holick, MD, PhD, told Musculoskeletal Report. "The baseline 25-OHD of 56 ng/mL is very unusual. No one has reported such high values, and the 21% increase in the levels is inconsequential. We see at least a 50% increase in patients taking 1000 IU/d." Dr. Holick from the vitamin D, skin, and bone research laboratory at Boston University Medical Center in Massachusetts recently published a major review of vitamin D deficiency.³

Dr. Francis said that the benefit of routine vitamin D plus calcium supplementation in prior studies was definite only for nursing home patients, who are likely to be vitamin D deficient. "Routine vitamin D supplementation as a public health measure appears ineffective, [except in] older care home residents, where there is a high prevalence of vitamin D insufficiency. In this situation, combined vitamin D and calcium supplementation should be used, as vitamin D alone appears ineffective."

Subjects in Fracture Prevention Trial of Intramuscular Vitamin D

• 9440 Subjects
  • 4354 Men
  • 5086 Women
• Median age 79.1 years
• 38% had previous clinical fracture
• Exclusion criteria: current cancer, treated osteoporosis, bilateral hip replacement, renal failure, renal stones, hypercalcemia or sarcoidosis, >400 IU/day of vitamin D supplements

Source: Smith et al.¹

Effect of Intramuscular Vitamin D on Fracture Risk in Elderly, Community-Dwelling Subjects

Fracture Site	HR With IM Vitamin D	P-value
Any nonvertebral	1.09	0.29
Hip or Femur	1.49	0.04
Wrist	1.22	0.28
Hip, femur, or wrist	1.40	0.02
Falls	0.98	0.50

Source: Adapted from Smith et al.¹

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