The relationship between pro-resorptive inflammatory cytokines and the effect of high dose vitamin D supplementation on their circulating concentrations.

Inflammatory/pro-resorptive cytokines and chemokines form part of a complex inter-dependent network and may be influenced by vitamin D. We investigated their inter-relationship and the effect of a loading dose of vitamin D. We measured plasma concentrations of an array of cytokines including tumour necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, IL-17, IL-8, granulocyte macrophage colony stimulating factor (GM-CSF), and the chemokine monocyte chemoattractant protein-1 (MCP-1). Cytokines, 25 (OH) vitamin D, 1,25 (OH)2 vitamin D, the Wnt inhibitor, DKK1 concentrations and bone turnover markers were measured at baseline and 3 months following a bolus dose (300,000 IU) of vitamin D2 in 39 subjects with vitamin D insufficiency. We observed strong correlations between TNF-α with GM-CSF (r=0.628, p<0.001), IL-17 (r=0.7, p<0.001) and MCP-1 (r=0.5, p=0.001), between IL-1ß with IL-17 (r=0.45, p=0.004) and between the 2 chemokines, IL-8 and MCP-1 (r=0.45, p=0.004). A positive correlation was seen between DKK1 and IL-1ß (r=0.35, p=-0.029). Following vitamin D loading at 3 months, the relationships between some of the cytokines changed (TNF-α and MCP-1: r=0.38, p=0.017, IL-1ß and IL-17: r=0.3, p=0.06). 1,25 (OH)2 vitamin D increased markedly following supplementation. Significant correlations were seen between 25 (OH) vitamin D (r=0.4 p=0.016) and 1,25 (OH)2 vitamin D (r=0.39 p=0.02) with plasma CTX (marker of bone resorption) at 3 months. TNF-α and IL-1ß increased significantly at 3 months (p<0.05). The close association between several cytokines is influenced by vitamin D status. Acute increases in 1,25 (OH)2 vitamin D, achieved with loading doses of vitamin D, lead to increases in pro-resorptive cytokines.

Efficacy of tibolone as "add-back therapy" in conjunction with a gonadotropin-releasing hormone analogue in the treatment of uterine fibroids.

OBJECTIVE: To assess the efficacy of tibolone add-back therapy with Goserelin treatment of uterine fibroids. DESIGN: Randomized placebo-controlled study. SETTING: Gynecology department of an inner-city teaching hospital. PATIENT(S): Seventy-five women of reproductive age with uterine fibroids. INTERVENTION(S): All women were given monthly SC implants of 3.6 mg goserelin and were randomized to take 3 months of placebo followed by 3 months of tibolone 2.5 mg daily (delayed administration), tibolone 2.5 mg daily for 6 months, or placebo for 6 months. MAIN OUTCOME MEASURE(S): Changes in bone mineral density (BMD) at the hip and spine, fibroid and uterine size, and patient symptomatology. RESULT(S): In the tibolone group, 2% loss of BMD at the spine was observed compared with 5.5% loss in the placebo group. For total hip, tibolone led to a 0.7% gain in BMD compared with a loss of 1.7% in the placebo group. Tibolone did not affect GnRH analogue-induced fibroid shrinkage. Vasomotor symptom scores in women taking tibolone were 2.2 and were significantly lower than those taking placebo or in the delayed administration groups (mean scores 2.9 and 2.7, respectively). CONCLUSION(S): Tibolone appears to be a safe and effective add-back therapy which can be given from the commencement of GnRH analogue treatment for fibroids.

The correction of BMD measurements for bone strontium content.

Strontium ranelate (SR) is a new oral treatment for osteoporosis associated with large increases in bone mineral density (BMD) compared with alternative therapies such as bisphosphonates. Much of the BMD increase during SR treatment is a physical effect caused by the increased attenuation of X-rays due to the accumulation of strontium in bone tissue. The aim of this study was to assess the contribution made by bone strontium content (BSC) to the overall BMD increase by evaluating the percentage F of the BMD change explained by the physical presence of strontium in bone. A value of F less than 100% would provide evidence of the anabolic effect of SR as an additional factor contributing to the overall BMD increase. Studies of mixtures of strontium hydroxyapatite (SrHA) and calcium hydroxyapatite (CaHA) scanned on a variety of dual-energy X-ray absorptiometry (DXA) systems show that a 1% molar ratio of SrHA/(CaHA+SrHA) causes a 10% overestimation of BMD. The correction of spine BMD measurements for the physical effects of strontium depends on knowledge of 2 further factors: (1) bone biopsy measurements of iliac crest BSC and (2) the ratio R of BSC at the DXA site to BSC at the iliac crest measured in animal studies. We used clinical trial data and values of R(spine) measured in studies of monkeys and beagle dogs to determine values of F(spine) for 1, 2, and 3 yr treatment with SR. Based on the average value of R(spine) approximately 0.7 for male and female monkeys, we found values for F(spine) approximately 75-80% for 1, 2, and 3 yr of treatment. Using the value of R(spine) approximately 1.0 from the beagle study gave values of F(spine) approximately 100%. Although values of F(spine) as low as 40% are possible, we conclude that the most likely figure is 75% or greater. However, it is apparent that there are large uncertainties in the correction of BMD results for the effect of bone strontium and that the most important of these is the inference of BSC values at DXA scan sites from measurements of iliac crest bone biopsy specimens.

The impact of vitamin D status on changes in bone mineral density during treatment with bisphosphonates and after discontinuation following long-term use in post-menopausal osteoporosis.

BACKGROUND: It is still unclear whether addition of calcium/vitamin D supplements leads to an incremental benefit in patients taking bisphosphonates and whether achievement of serum level of 25 (OH) vitamin D of at least 70 nmol/L has an impact on the skeletal response to bisphosphonates. Moreover the maintenance of BMD after bisphosphonates withdrawal with the continuation of calcium/vitamin D supplements only, remains uncertain. The aims were to assess the impact of vitamin D status on changes in bone mineral density (BMD) in firstly patients with post-menopausal osteoporosis on bisphosphonates and secondly following discontinuation of bisphosphonates after long-term use. METHODS: Two patient groups were recruited. The first study population comprised of 112 women treated with a bisphosphonate. The second study population consisted of 35 women who had been on bisphosphonates for > 5 years in whom the treatment agent was discontinued. Baseline BMD, changes in BMD following treatment, duration of treatment, serum 25 (OH) vitamin D, parathyroid hormone (PTH), urine C-terminal telopeptides of type 1 collagen (CTX) were obtained on the study participants. RESULTS: In the first study group, subjects with serum vitamin D concentrations (> 70 nmol/L) had a significantly lower serum PTH level (mean [SEM] 41 2 ng/L). PTH concentrations of 41 ng/L or less was associated with a significantly higher increase in BMD at the hip following treatment with bisphosphonates compared to patients with PTH > 41 ng/L (2.5% [0.9] v/s -0.2% [0.9], P = 0.04). In the second study group, discontinuation of bisphosphonate for 15 months after long-term treatment did not result in significant bone loss at the lumbar spine and total hip, although a trend towards gradual decline in BMD at the femoral neck was observed. CONCLUSION: the data suggest that optimal serum 25 (OH) vitamin D concentration may lead to further reduction in bone loss at the hip in patients on bisphosphonates. A prospective controlled trial is needed to evaluate whether the response to bisphosphonates is influenced by vitamin D status. BMD is preserved at the lumbar spine and total hip following discontinuation of bisphosphonate for a short period following long-term treatment, although a gradual loss occurs at the femoral neck.

Effects of dietary improvement on bone metabolism in elderly underweight women with osteoporosis: a randomised controlled trial.

Malnutrition in elderly people contributes to osteoporosis and fracture. The aim of the study was to investigate the effects of nutritional improvement on bone metabolism in elderly community-dwelling women. A 12-month randomized controlled trial of 71 ambulant women aged > or =70 years with BMI < or =21 kg/m(2 )and osteoporosis at the hip was undertaken. They received either calcium (1 g) and vitamin D (800 units of cholecalciferol) only (group 1: n=35) or calcium/vitamin D and one or two cartons of a nutritional supplement drink which provided 300 Kcal, 12 g protein, 11.6 g fat and 36.8 g carbohydrate per carton (group 2: n=36). Body composition and bone mineral density (BMD) were assessed at baseline and 12 months. Biochemical markers of bone turnover were measured at baseline and at 1, 3, 6, 9 and 12 months. Group 2 gained significantly more weight [mean (SD) group 1: 0.15 (2.45), group 2:2.66 (2.8) kg P<0.001] and fat mass [group 1: -0.26 (1.8), group 2:1.9 (1.7) kg P<0.001]. BMD at the spine, femoral neck and total hip did not change significantly, although there was a positive trend at the total hip in group 2 [group 1: -0.5 (5.2), group 2:1.25 (3.3)%, P=0.13]. In a subgroup analysis, irrespective of their treatment group, there was a significant difference in changes in BMD at the lumbar spine and total hip in those who lost body weight (A) compared to those who had maintained or increased their weight (B), [mean (SD) % change in BMD lumbar spine; A: -1.64 (3.75), B: 0.96 (2.75) P=0.013, total hip A: -2.09 (6.0), B: 1.04 (3.3), P=0.05)] A significant reduction in serum CTX, a marker of bone resorption, was seen in group 2 [% decrease at 3 months, group 1: 1 (8.7), Group 2: 32 (5.8), P<0.01]. Serum osteoprotegerin (OPG) increased significantly in group 2 with a maximal increase (27%) observed at 6 ( P<0.01) and 9 months ( P<0.05). A small increase in bone-specific alkaline phosphatase was seen at 12 months in group 2 [% increase group 1:5 (5), group 2: 17 (6), P=0.05]. Serum osteocalcin increased at 12 months in group 2 ( P=0.01). Dietary improvement in elderly women with low BMI is associated with a reduction in bone resorption with a small but "net" positive effect on bone formation.