Vitamin D status in non-supplemented postmenopausal Taiwanese women with osteoporosis and fragility fracture

Osteoporosis is a progressive systemic bone disease characterized by low bone mass and microarchitecture deterioration of bone tissue, leading to increased bone fragility and susceptibility to fracture. It is recognised as a major public health problem in many countries, as well as in Taiwan[1, 2]. The fractures associated with osteoporosis cause physical disability, reduced quality of life and high mortality in the aging population[3, 4]. Several therapeutic options are available for the treatment or prevention of osteoporosis[5, 6], and some of these drugs were proven to be efficacious and safe in Taiwanese population studies[7‐10]. Among the osteoporosis management factors, vitamin D plays an important role[11, 12]. Vitamin D is absorbed from food or synthesized in skin that is exposed to sunlight. The liver converts it to 25-hydroxyvitamin D [25(OH) D], which in turn is converted by the kidney to active form calcitriol 1,25 (OH)₂D. Vitamin D increases serum calcium by promoting intestinal calcium absorption and plays a role in bone formation and resorption[13]. Synthesis of 1, 25-dihydroxyvitamin D [1, 25(OH)₂ D] is stimulated by both PTH and hypophosphatemia. Vitamin D deficiency is associated with secondary hyperparathyroidism, which stimulates bone resorption, thus increasing the rate of bone loss and the risk of fractures[14]. In addition, vitamin D deficiency is associated with muscle weakness and postural instability, leading to an increased risk of falls[15], which may lead to fractures. However, vitamin D status associated with fractures has not been investigated in the Taiwanese population. The objective of this study was to evaluate the prevalence of vitamin D inadequacy among postmenopausal women with osteoporosis and fragility fractures of the hip or vertebrae in Taiwan.

A total of 199 subjects were evaluated for inclusion with 194 subjects meeting all of the eligibility criteria as shown in Figure 1. Five subjects were excluded due to renal or liver impairment (4 subjects with Cr > 1.6 mg/dL and 1 subject with ALT > 3 times ULN). The demographics and characteristics of the patients are shown in Table 1. Overall, the average age was 77.6years (range: 52 to 103 years) and the mean BMI was 23.9 kg/m². The mean years since menopause were 27.4 with a minimum of 5 years and maximum of 51 years. There was no difference of BMD at any site between the hip and vertebral fractures group.

Overall, the mean level of 25(OH) D was 21.1 ± 9.3 ng/mL, ranging from 4.0 to 57.5 ng/mL (median: 20.0, Q1:15.7, Q3:26.2). The prevalence of vitamin D inadequacy with serum 25(OH) D level lower than 30 ng/mL was 86.6% of the subjects. Further dissection, vitamin D insufficiency [25(OH) D 10–30 ng/mL] prevalence was 77.8% while vitamin D deficiency [25(OH) D < 10 ng/mL] was 8.8% of the subjects (Table 2). Additionally, when using another cut-off point of 25(OH) D < 20 ng/mL, the prevalence was 49.5%, as shown in Table 3.

There was no statistically significant difference in the mean 25(OH) D levels between hip and vertebral fractures subjects, 20.5 vs. 22.0 ng/mL, respectively (p = 0.279; Table 4). In terms of serum markers, in the hip fracture group, there were significantly higher mean i-PTH levels (45.7 vs. 35.8 pg/mL), lower mean serum calcium (8.2 vs. 8.9 mg/dL), lower mean serum phosphorus (3.5 vs. 4.2 mg/dL) and lower mean BAP levels (13.0 vs. 18.2 mg/dL) compared to vertebral fracture group (Table 4). Serum creatinine and alanine aminotransferase were similar between the groups. The mean vitamin D levels were slightly higher but no statistical difference in summer and fall than in winter and spring season.

When analyzing the mean serum 25(OH) D levels and prevalence using three cut-off points (<30, <20 and < 10 ng/mL) by different age groups (<60; 60 ~ 69; 70 ~ 79; 80 ~ 84; ≥85 years), the results were consistent across all age groups with no statistical difference in the vitamin D levels or proportion of patients with vitamin D levels lower than 30 ng/mL, 20 ng/mL or 10 ng/mL in any of the age groups (Table 5).

This is the first study to examine the prevalence of vitamin D inadequacy among osteoporotic women with fragility hip or vertebral fracture in Taiwanese population. The results of this study have shown a high prevalence of vitamin D inadequacy (insufficiency and deficiency) across all age groups among women with fragility hip or vertebral fracture in Taiwan. Some studies conducted in Taiwan and Asia have shown nearly half of healthy, middle-aged and elderly women had vitamin D inadequacy, nearly one-third of adults with frailty syndrome had vitamin D insufficiency[19, 20] and inadequacy levels are more common in some Asian countries than in other regions[21].

International Osteoporosis Foundation recommends that a minimum level of 30 ng/mL 25(OH) D is necessary in older adults to reduce the risk of falls and fractures[15]. Some guidelines suggest a 25(OH) D level of at least 20 ng/mL to promote intestinal calcium absorption, avoid secondary hyperparathyroidism and minimize the risk of fracture[22]. In our study, the prevalence of vitamin D insufficiency, 25(OH) D level lower than 30 ng/mL, was 86.6% and the prevalence of 25(OH) D lower than 20 ng/mL was 49.5%. As compared to the National Health and Nutrition Examination Survey (NHANES) 2005 to 2006, where 41.6% of adults had 25(OH) D below 20 ng/mL[23], in the current study we have found a higher proportion of vitamin D insufficiency (49.5%, vs. 41.6%), probably due to inclusion of subjects with confirmed fragility fracture either admitted to hospital or from outpatient clinics and due to exclusion of patients taking vitamin D supplementation regularly (2800 IU vitamin D per week or 400 IU vitamin D per day). The results were consistent with the previous findings that low vitamin D levels were associated with a high hip fracture rate[24] and other osteoporotic fractures, including vertebral and wrist fractures[25]. One recent study has shown that among patients admitted to a rehabilitation facility, 49.1% had 25(OH) D levels below 20 ng/mL and 83% lower than 30 ng/mL[26], which is consistent with the current study results. Another study in the literature has shown 68% of hypo-vitaminosis D in an orthogeriatric rehabilitation ward within 7 days after hip fracture[27].

Vitamin D plays an important role in protein synthesis and the regulation of calcium transport which affects muscle strength as well as the balance among neurons and muscle. This might be the reason why vitamin D deficiency has been associated with muscle weakness and postural instability, leading to an increased risk of falls, which may lead to fractures[28, 29]. Low vitamin D levels are also associated with decline in physical performance in the elderly[30].

The relationship of 25(OH) D level and i-PTH is consistent with previous reports that the synthesis and metabolism of vitamin D is coupled to calcium homeostasis and is regulated by PTH, serum calcium and phosphorus levels[12]. When hypocalcaemia occurs, serum PTH concentration increases and enhances reabsorption of calcium. In our study, serum 25(OH) D was inversely correlated with serum i-PTH (r = -0.22, p < 0.01).

The possible explanations for the high prevalence of vitamin D insufficiency in this cohort of Taiwanese women could be several. First, the Recommended Dietary Allowance (RDA) of vitamin D for the elderly is 800 international units per day after age 71[22], but only 17.5% subjects have vitamin D supplements in daily life and larger-dose preparations of ergocalciferol or cholecalciferol are rare in Taiwan. Second, the consumption of fatty fish, vitamin D-fortified foods and vitamin D supplements also influence the status of vitamin D insufficiency[31, 32]. This is the largest source of dietary vitamin D in many countries, but fortified milk, cereals and bread products with vitamin D in Taiwan are rarely found. Therefore, vitamin D from dietary source might be limited due to less options and lower availability of vitamin D-containing food in addition to decreased intestinal absorption of vitamin D in elderly patients. Third, the vitamin D status depends on the available amount of ultraviolet light from sunlight which varies with latitude and season; use of sunscreen and clothing; and amount of sunlight exposure which increases vitamin D concentration[33]. Although Taiwan is situated at latitude between 23 and 25 degrees, sun-avoidance behavior, skin covering and the use of sunscreen products in the Taiwanese population interfere with production of vitamin D in the skin. In addition, the serum vitamin D level has been shown to decrease with aging, with the skin of those older than 70 years of age being less efficient in converting 7- dehydrocholesterol into vitamin D as compared to younger individuals, impairing dermal biosynthesis of vitamin D[34].

There are some limitations of the current study. The sample size of this study (n = 194) was relatively small although well spread and distributed throughout the island. Also, this study did not include healthy subjects without fractures or male gender as normal controls. Another limitation was the study design which did not allow us to collect vitamin D levels at the exact time of fracture; however, it was not expected that levels of vitamin D would vary significantly in the short period of time stipulated for blood collection after fracture.

High prevalence of vitamin D insufficiency and deficiency was found among post-menopausal women with osteoporosis and fragility hip or vertebral fracture in the Taiwanese population. Recommendations and public education for postmenopausal women with osteoporosis to receive adequate vitamin D supplementation should be reinforced.