We found a strikingly high prevalence of vitamin D deficiency paralleled by secondary hyperparathyroidism in patients with peripheral arterial disease. It appears to us that vitamin D deficiency is an underestimated complication in patients with PAD.
Impaired vitamin D metabolism is accompanied by insufficient intestinal calcium absorption and renal calcium loss, resulting in secondary hyperparathyroidism and, ultimately, osteomalacia.7,9
Symptoms typical for osteomalacia, such as arthralgia, paresthesia, fatigue, muscle pain and weakness, deep bone pain, and difficulties in walking, are frequently described in these patients and contribute significantly to the clinical picture of PAD. Common causes of vitamin D deficiency, including impaired renal function, malnutrition, malabsorption, hepatic failure, or bone-active drugs9,10,26,34
were excluded from our study. Nevertheless, our population was an elderly one, and age is associated with decreasing vitamin D3
synthesis and storage in the skin as well as decreased absorption in the gut and kidneys. It is, however, well known that restricted mobility with subsequent lack of sunlight exposure leads to vitamin D deficiency, even in patients with normal renal function.13,14,16,22,33,34,38–40
Patients with PAD, especially those with local ulcers, are frequently immobilized by pain and may become socially isolated. The lack of sunlight exposure caused by partial or total immobility would be a reasonable explanation for the deficiency or inadequacy of vitamin D even in the absence of renal or liver disease or bone-active medication. On the basis of this hypothesis, we were able to show significantly lower vitamin D3 and serum calcium levels in patients with PAD grade IV than in patients with PAD grade II or control subjects. It must be pointed out that there were no differences when the latter 2 groups were compared to each other. Vitamin D deficiency was found in more than 70% of PAD grade IV patients, of which osteomalacia could be assumed in 31%, with serum vitamin D3 levels even below 5 ng/mL. Even though vitamin D deficiency is common in the elderly, the magnitude of the problem in PAD patients was surprising. That we found no correlation of vitamin D3 to the patients' age in the study population may be due to the narrow age range of our patient group.
We found elevated iPTH values in patients with decreased serum vitamin D3
levels, as previously described.10,41
The prevalence of secondary hyperparathyroidism in our study was only 40% in Group B patients, a relatively low value despite a high prevalence of vitamin D deficiency (71%). Chapuy et al. described an increased iPTH level in virtually all elderly subjects investigated despite a prevalence of hypovitaminosis D of only 39%, but they studied only older women and did not exclude those with impaired renal function.41
In contrast, Thomas et al. described a relatively low percentage of severe vitamin D deficiency (<9 ng/mL) of 22% in younger medical inpatients, although many of the patients had impaired renal or liver function or co-medications with known influence on vitamin D metabolism.10
The discrepancy between this study and our findings may be due to the fact that those patients were younger and hospitalization only lasted for a few days—not long enough to deplete vitamin D stores that are likely to be higher in these patients than in ours, because their patients were younger and mobile prior to hospitalization. Another possible explanation may be the fact that fortified milk or dairy products are not available in Austria.
Surprisingly, the duration of the disease had no influence on vitamin D status in our patients. There is some evidence that vitamin D depletion occurs within a relatively short time.16,20
We included only patients with a PAD history of at least 6 months. After this time, vitamin D depletion already seems to be established.
The individual disability score was a major determinant of vitamin D status in our study. Bischoff et al. described a decrease of vitamin D3
combined with elevated bone resorption markers with increasing immobility in a population of residents of a geriatric ward stratified by a grade 4 mobility score.42
In another study, patients with a high personal outdoor score had higher vitamin D3
and lower iPTH levels than more-or-less homebound individuals.41
Our patients were categorized in a similar fashion and were asked to quantify their personal assessment of being restricted and housebound by their disease. Subjects who felt severely disabled had significantly lower vitamin D3
and higher serum iPTH levels than those who described themselves as only mildly restricted, regardless of the stage of PAD. This finding again supports our hypothesis that lack of sunlight exposure is the key factor for the development of vitamin D3
deficiency. As mobility decreases, the problem increases, since vitamin D deficiency aggravates fatigue, muscle weakness, and bone pain. In parallel, PAD progresses with decreasing mobility and lack of exercise, creating a vicious cycle from which patients cannot escape. Another interesting aspect could be that vitamin D–deficient individuals may be at high risk of developing PAD due to fatigue, pain, and the consequent lack of exercise.
A low serum vitamin D3
concentration is not a simple biochemical abnormality. Pfeifer et al. have described how hypovitaminosis D is associated with increased body sway and an elevated risk for falls and fall-related fractures.43
Because vitamin D3
is required for calcium homeostasis, secondary hyperparathyroidism may develop in patients with vitamin D deficiency who are on a normal- or low-calcium diet. With increasing severity of vitamin D deficiency and secondary hyperparathyroidism, patients may progress from initially increased bone turnover to greatly impaired mineralization with generalized osteomalacia.
We found significantly higher osteocalcin levels in patients with PAD grade IV as compared to Group A, indicating increased bone turnover. The present study is of course limited by the absence of measurements of resorption markers and/or bone density. Nonetheless, surrogates of bone metabolism, such as ALP, the most commonly used marker for hypovitaminosis D osteopathy,12,44,45
as well as OC as a further parameter for this condition,46
were significantly higher in patients in Group B than in those in the other groups. A higher prevalence of osteopathy is therefore likely in at least some of these patients. Falls and bone fractures may also aggravate the clinical condition of PAD patients. Further studies are needed to elucidate whether the biochemical findings in our study would also document low bone mass, osteoporosis, and increased fracture incidence in PAD.
There is evidence that vitamin D–deficient patients profit from simple vitamin D3
and, after a few months of substitution, muscle strength improves remarkably.44,45,48,49
There is evidence that calcium and vitamin D3
substitution significantly reduce the risk of falls and therefore the incidence of bone fractures.49–53
The magnitude of vitamin D depletion in our patients justifies regular and routine monitoring of vitamin D status in the management of patients with peripheral arterial occlusive disease. In the elderly populations of industrialized countries, PAD has a known prevalence of about 10%, and there is evidence for even more unrecognized cases.54
Management of PAD, therefore, raises public health expenditures for specific therapy and additional medication and physiotherapy for such symptoms and consequences of vitamin D deficiency and osteomalacia as fatigue, myalgia, muscle weakness, bone pain, and fractures.
Replacement therapy with vitamin D3 could be an inexpensive, well-tolerated, and highly effective supportive treatment to mitigate pain and the risk of falls with subsequent bone fractures, and ultimately to improve the quality of life and outcome in PAD patients. Further studies should investigate the influence of vitamin D3 replacement therapy on quality of life and outcome in this special group of patients.