Invited critical review
Bone resorption markers in vitamin D insufficiency

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Abstract

Severe vitamin D deficiency (serum 25 hydroxyvitamin D (25(OH)D) below 12.5 nmol/L) causes rickets and osteomalacia, but there is good evidence that lesser degrees of hypovitaminosis D (vitamin D insufficiency) have deleterious effects on bone and other organs. Evidence of impaired mineralization, suggestive of vitamin D insufficiency, has been found in bone biopsies of hip fracture patients in the UK, and several studies around the world have shown a rise in serum parathyroid hormone (PTH) as 25(OH)D levels fall below 50 nmol/L. Fifty-seven percent of hospital inpatients in a Boston study had vitamin D insufficiency and their serum 25(OH)D showed an inverse relationship to their serum alkaline phosphatase (ALP) levels. Thirty-five percent of outpatients had vitamin D insufficiency in an Adelaide study, where ALP and urine hydroxyproline and pyridinium cross-links were all inversely related to serum 25(OH)D.

The increased bone resorption of vitamin D insufficiency is important on two counts. Firstly, increased bone resorption may lead to increased bone loss and osteoporosis and, secondly, increased turnover appears to increase fracture risk in its own right.

A consensus is developing that serum 25(OH)D levels should be maintained at 50 nmol/L or greater in the elderly to minimize the occurrence of fractures. In addition, it appears that optimal levels of bone resorption markers in this population are at or just below the mean level for premenopausal women.

Section snippets

Vitamin D deficiency

Severe vitamin D deficiency causes rickets in children and osteomalacia in adults, is associated with hypocalcaemia, impaired mineralization of bone, muscle weakness and deformity (in children), and produces the characteristic radiographic findings of flaring of the epiphyses (in children), Looser's zones (fissure fractures) and ill-defined trabeculae [6]. Bone biopsies show increased amounts of unmineralized bone matrix (osteoid) and decreased mineralization lag time (measured with double

Vitamin D insufficiency

There is general agreement that low vitamin D levels, above those causing overt osteomalacia, lead to increased bone loss and an increased risk of fracture. Levels of 25(OH)D less than 12.5 nmol/L are associated with osteomalacia, while levels between 13 and 50 nmol/L indicate vitamin D insufficiency [8]. First hints of this condition came from studies of bone biopsies in hip fracture patients in the UK [9], [10]. Hip fracture patients (102 women and 23 men) had more unmineralized osteoid in

Secondary hyperparathyroidism in vitamin D insufficiency

The increase in serum parathyroid hormone (PTH), which occurs as serum 25(OH)D levels fall, is generally attributed to the decreased calcium absorption, which accompanies low 25(OH)D levels [7], [19]. There is an inverse relation between PTH and serum ionized calcium, indicating secondary hyperparathyroidism, in postmenopausal women in Australia [20], but the relation between serum 25(OH)D and calcium absorption is weak and the change in calcium absorption noted when 25(OH)D levels rise in

Prevalence of vitamin D insufficiency

Thomas et al. reported in 1998 that hospitalized male and female US patients have low levels of 25(OH)D [25]. It is perhaps more surprising that ambulant postmenopausal women in sunny South Australia had low levels [20], or even that randomly selected members of the US community in the NHANES III study [26] and normal adolescents in Tasmania [27] were at risk of vitamin D insufficiency (Table 1).

Vitamin D and bone resorption

It is well known that vitamin D deficiency (osteomalacia) causes an increase in bone resorption (presumably from the rise in PTH caused by hypocalcaemia) and a rise in serum ALP is considered a cardinal feature of the syndrome. However, bone markers are also raised in patients with vitamin D insufficiency. In the study of hospital inpatients already mentioned [25], there was an inverse relationship between serum 25(OH)D and serum alkaline phosphatase (ALP). Sahota et al. reported that UK women

Bone turnover markers and fracture risk

Several prospective studies indicate that increased bone turnover predicts increased fracture risk. Garnero et al. [31] reported in 1996 that markers of bone resorption predicted hip fractures in elderly women in the EPIDOS study, and Ross et al. showed later that bone ALP predicted both vertebral and non-vertebral fractures in postmenopausal community-dwelling women [32]. Riggs et al. have shown that vertebral fracture reduction in a randomized trial of estrogen in postmenopausal women was due

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