Vitamin D is well known for its pivotal role in calcium homoeostasis. As bone is the principal calcium store in the body, a relationship between vitamin D and bone health can be expected. Vitamin D deficiency was identified as the underlying cause of rickets and osteomalacia, the adult form of rickets. Rickets and osteomalacia are characterized by softening of the bones resulting in deformation and fractures. Both these conditions are caused by a defect in the mineralization of the bone’s protein framework known as osteoid. This defective mineralization is mainly caused by a lack of vitamin D. In developing countries where poor nutrition remains a problem, rickets and osteomalacia can still be seen on a regular base. While extreme manifestations of vitamin D deficiency are rare in developed countries, the effects of suboptimal vitamin D levels are common. Osteoporosis is one such example that affects approximately 200 million individuals worldwide. Osteoporosis is a degenerative condition characterized by a loss of bone mass, reduced biomechanical bone properties, and an increased fracture risk.
A low serum 25(OH)D concentration is usually associated with a small decrease of serum 1,25(OH)2D and a reduced calcium absorption. This subtle change is sensed by the calcium-sensing receptor resulting in an increased secretion of PTH from the parathyroid glands. This condition is referred to as secondary hyperparathyroidism (sHPT). sHPT is characterized by elevated serum PTH, low circulating 25(OH)D, but normal (or mildly decreased) 1,25(OH)2D and calcium levels. PTH stimulates renal 1,25(OH)2D synthesis and mobilizes calcium from bone. This results in bone loss, primarily affecting cortical bone. It is believed that sHPT is the principal mechanism whereby vitamin D deficiency contributes to bone loss and fragility fractures (1). However, not all individuals with low 25(OH)D levels develop sHPT. Serum PTH correlates negatively with serum 25(OH)D (1) (Fig. D6).
Seasonal Variation of vitamin D and bone turnover
Vitamin D synthesis and consequently circulating 25(OH)D levels are subject to a substantial seasonal variation which is due to low UV-B irradiation during autumn and winter. Individuals showing borderline or a low-normal concentration of 25(OH)D at the end of summer or in autumn are typically deficient at the end of winter. Therefore, the preferred time to diagnose vitamin D deficiency is in spring. The seasonal variation of 25(OH)D levels results in a marked seasonal variation of bone turnover. A population-based German study including 580 adults showed higher values of the bone turnover markers bone alkaline phosphatase and urinary pyridinoline in winter than in summer (2). Also in patients with osteomalacia bone turnover markers are elevated when compared to healthy control subjects. Therefore, biochemical markers of bone turnover may be helpful in diagnosing functional vitamin D deficiency (3) (Fig. D7).
Bone Mineral Density (BMD) is a strong predictor of fracture risk. Considering the relationship between vitamin D levels and fracture risk a significant association between vitamin D and BMD can be expected. At present the most compelling evidence for such an association is provided by the National Health and Nutrition Examination Survey III (NHANES III) (4). In this study BMD continuously increased up to 25(OH)D levels of 94 nmol/L in all subgroups.
Vitamin D deficiency causes bone mineral loss by several mechanisms including an increased formation of un-mineralized osteoid and a lower degree of mineralization at sites where mineralized bone is formed. Vitamin D deficiency also leads to a negative bone remodeling balance per osteon. The irreversible cortical bone loss appears to be due to endosteal bone resorption and subsequent cortical thinning (5) (Fig. D6).
Fragility fractures are the most common complications of osteoporosis with often devastating consequences for the affected individual. The highest level of evidence for a relationship between serum 25(OH)D and fracture risk comes from prospective studies (6;7) (Fig. D8 and D10). Recent large epidemiologic studies clearly show a significant association between serum 25(OH)D and hip fractures in elderly individuals (7;8) (Fig. D9). However, for younger individuals and other fracture sites the relationship between serum 25(OH)D and fracture has not yet been proven. Results from the “Women’s Health Initiative Study” provide the most compelling evidence for an association between serum 25(OH)D and fracture risk (8). The average follow-up time was 7.1 years. A 25 nmol/L decrease in 25(OH)D was associated with a 33% increased risk of hip fracture (odds ratio OR = 1.33; 95% CI = 1.06 – 1.68). In women with a serum 25(OH)D level < 47.5 nmol/L the OR of hip fracture was 1.71 (95% CI = 1.05 – 2.79) when compared to women with serum 25(OH)D levels ≥ 70.7 nmol/L. Measurement of bone turnover markers showed that this association was in part mediated by bone resorption.
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