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Context: Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS); however, there is no medication that has been approved specifically to treat MS-related fatigue. Objective: We aimed to evaluate the effect of vitamin D analogue, Alfacalcidol, on MS-related fatigue. Design, settings, participants: This was a randomized, double-blind, parallel group, placebo-controlled trial in patients with clinically definite MS by McDonald criteria conducted in a single university-affiliated medical center in Israel. Randomly selected patients from the Sheba MS Registry computerized database (N=600) were assessed using the self-report Fatigue Severity Scale (FSS). Patients with clinically meaningful fatigue (N=259) were further assessed for trial eligibility, and MS patients with significant fatigue (N=158; 61%, 118 females, mean age 41.1 ± 9.2 years and mean disease duration of 6.2 ± 5.5 years) were included in the study and randomized to receive treatment or placebo. Intervention: Alfacalcidol (1 mcg/d, N=80) or placebo (N=78) was administered for six consecutive months. Main outcome measure: The primary endpoint of the study was the change between Alfacalcidol and placebo-treated patients in the Fatigue Impact Scale (FIS) score; the cut-off point for improvement was defined as 30% decrease. All analyses followed the intention-to-treat principle and were performed for all participants based on the group they were randomly allocated regardless of whether or not they dropped out. Results: Alfacalcidol decreased the mean relative FIS score as compared with placebo (–41.6% vs. –27.4%, p=0.007, respectively). This advantage was further emphasized when the modified FIS (MFIS) relative change was calculated. Quality of Life (QoL) improved in Alfacalcidol-treated patients as compared with placebo in the RAYS psychological (p=0.033) and social (p=0.043) sub-scales. The Alfacalcidol-treated group had reduced number of relapses (p=0.006) and higher proportion of relapse-free patients (p=0.007). Reduction of relapses by Alfacalcidol became significant at 4 months of treatment, was sustained at 6 months and decayed 2 months after drug discontinuation. Alfacalcidol treatment was safe and no serious adverse events were recorded. Conclusion: Alfacalcidol is a safe and effective treatment strategy to decrease fatigue and improve QoL in patients with MS.

SummaryIntestinal fractional calcium absorption (FCA) was assessed before and after vitamin D3 treatment. Serum 1,25(OH)2D concentration was significantly increased by plain vitamin D3 and reduced by eldecalcitol. The 1α hydroxyl calcidiol and eldecalcitol treatments increased FCA, which may be induced through direct stimulation of vitamin D receptors in the intestine.IntroductionTo assess the effects of vitamin D3 compounds on intestinal FCA and calcium-regulating hormones in post-menopausal osteoporosis, a randomized open-label prospective study was conducted.MethodsForty eligible patients were allocated randomly into four groups: eldecalcitol (ELD; 0.75 μg/day), 1α hydroxyl calcidiol (ALF; 1 μg/day), plain vitamin D3 (800 IU/day), and control. Before and after the 4-week treatment, intestinal FCA was estimated by using a double isotope method, and serum concentrations of calcium-regulating hormones and a bone turnover marker were measured.ResultsThe baseline FCA value of the participants was 21.5 ± 7.9% (mean ± SD) and was significantly correlated with serum 1,25(OH)2D (calcitriol) concentration. After the treatment, the FCA significantly increased by 59.5% (95% CI, 41.6 to 77.4%) in the ELD group and by 45.9% (27.9 to 63.8%) in the ALF group, whereas no significant change in the plain vitamin D3 group was found. Unlike the baseline FCA, post-treatment FCA exhibited no significant correlation with serum calcitriol concentration. Parathyroid hormone levels were suppressed by ALF and plain vitamin D3 but were sustained in the ELD and control groups. Serum calcitriol tended to be suppressed by ELD, whereas plain vitamin D3 treatment increased both serum 25(OH)D and calcitriol concentrations.ConclusionThese findings suggest that oral administration of vitamin D3 analogues (ALF and ELD) stimulates FCA but plain vitamin D3 does not. Those effects of vitamin D3 compounds on FCA were independent of serum calcitriol concentration, suggesting that ALF and ELD may directly stimulate intestinal vitamin D receptors.

The aim of this study was to evaluate the effect of perioperative alfacalcidol on postoperative hypocalcemia after total thyroidectomy. A total of 219 patients scheduled for total thyroidectomy were randomized into groups not receiving (group A) or receiving (group B) perioperative alfacalcidol. Postoperative hypocalcemia was compared between groups on postoperative day (POD) 1 and POD2. Patients with hypocalcemia (<2.00 mmol/L) received oral calcium supplementation. Calcium and vitamin D levels were measured at 5-week and 6-month follow-ups. The incidence of symptomatic hypocalcemia was significantly lower in group A (P = .02), whereas similarly low levels of calcemia were observed in both groups on POD1 (37% and 30%, respectively; P = not significant) and persisted on POD2 (14% and 6%, respectively; P = not significant). Patients with severe hypocalcemia (<1.90 mmol/L) showed faster recovery in group A compared with group B (6% vs 1%, P = .04). At 5 weeks, calcium and vitamin D levels were similar between the groups. Six months after surgery, 4% (group A) versus 0% (group B) of subjects exhibited permanent hypoparathyroidism (P = .04). Although the treatment did not correct vitamin D deficiency, perioperative alfacalcidol uptake resulted in decreased transient hypocalcemia and related symptoms in patients undergoing total thyroidectomy.

We conducted a prospective multicenter study to assess early changes in the dynamics of bone metabolism in patients with systemic connective tissue diseases following commencement of high-dose glucocorticoid therapy and the benefits of early treatment with bisphosphonate and vitamin D analogue. The subjects of this randomized controlled trial were 106 female patients with systemic connective tissue diseases treated for the first time with glucocorticoids at doses equivalent to prednisolone ≥20 mg/day (age ≥ 18 years). One week after initiation of glucocorticoid therapy, patients were randomly assigned to treatment with alfacalcidol at 1 μg/day ( n  = 33), alendronate 35 mg/week ( n  = 37), and alfacalcidol plus alendronate ( n  = 36). The primary endpoints were changes in lumbar spine bone density at 6 months of treatment and the frequency of bone fracture at 12 months. Commencement of glucocorticoid therapy was associated with a rapid and marked bone resorption within 1 week. The combination of alfacalcidol and alendronate administered after the first week of glucocorticoid therapy halted the pathological processes affecting bone metabolism, increased bone density, and reduced the incidence of bone fracture over a period of 12 months. Taken together, the use of the combination of alfacalcidol and alendronate improved bone metabolism, increased bone density, and significantly reduced the incidence of bone fracture during 1-year high-dose glucocorticoid therapy.

Background Vitamin D supplements are recommended in individuals with vitamin D insufficiency and established osteoporosis to reduce risk of fracture and falling. Active vitamin D metabolites have been found to be more effective for fall prevention than native vitamin D. Objectives The aim of this study was to compare the efficacy of strontium ranelate in combination with alfacalcidol and strontium ranelate alone on bone mineral density (BMD) and fall risk in postmenopausal women with osteoporosis. Methods A total of 48 women (mean age 62.4 years) with postmenopausal osteoporosis were randomized to strontium ranelate monotherapy 2 g/day ( n  = 16), strontium ranelate 2 g/day plus alfacalcidol 1 μg ( n  = 16) or control ( n  = 16) and followed for 6 months. All women received calcium and vitamin D 3 supplements. BMD was measured at the lumbar spine and proximal femora at the beginning and end of therapy. Patients performed functional tests such as the “up and go” and chair rising tests to estimate risk of fall status. Biochemical markers of bone turnover were also assessed. Results Statistically significant increases in BMD compared with baseline values and the control group were observed in both strontium ranelate treatment groups. Increases were also statistically significant in the strontium ranelate combination group compared with strontium ranelate alone. Strontium ranelate combination therapy for 6 months improved patients’ ability to perform functional tests as well as increasing the number of women capable of performing the tests. No significant changes were observed in women receiving strontium ranelate monotherapy or in the control group. Serum levels of β-CrossLaps, a marker of bone resorption, were significantly reduced compared with control in both strontium ranelate groups. A significantly greater reduction was observed in the strontium ranelate combination group compared with strontium ranelate alone (24.0 %; P  = 0.008). Increases in type 1 procollagen total N-terminal propeptide (TP1NP), a marker of bone formation, reached statistical significance in both strontium ranelate groups compared with baseline. Conclusion Strontium ranelate and alfacalcidol combination therapy improves bone quality, fall risk and markers of bone turnover to a greater extent than strontium ranelate alone in patients with established osteoporosis.

A prospective randomized study for prevention of postrenal transplantation bone loss. We aimed to investigate different treatment drugs for the prevention of post-transplant bone loss. Sixty adult male recent renal transplant recipients were enrolled into the study. Patients were randomized into 4 groups: group I received daily alfacalcidol 0.5 μg PO; group II received oral alendronate 5 mg/day; group III received intranasal salmon calcitonin 200 IU every other day; and group IV was considered a control group. Every patient was supplemented with daily 500 mg oral calcium carbonate. Parameters of bone metabolism were measured before and at 12 months after starting treatment. Bone mineral density (BMD) was measured by (DEXA) at lumber spine, femoral neck, and forearm before and after treatment period. BMD was increased at lumber spine by 2.1%, 0.8%, 1.7%, by 1.8%, 0.6%, 1.6% at femoral neck, and by 3.2%, 1.9%, 2.6% at forearm in groups I, II, and III, respectively, while it decreased by 3.2%, 3.8%, and 1.8% at the same sites, respectively, in control group (P = <0.05). iPTH level decreased significantly in group I, while the decrease was insignificant in other groups (P = 0.003). All other parameters were not statistically significant between treatment groups. Apart from transient hypocalcaemia in 3 patients in group II, and 2 patients in group III, no other significant adverse effects were noted. This study proves that early bone loss that occurs during the first 12 months after renal transplantation could be prevented by alfacalcidol, calcitonin, or alendronate. Among the treatment groups, alfacalcidol significantly improved the hyperparathyroidism. All treatment drugs are safe and tolerable.

ObjectiveRemoval of the ovaries is common during surgery for endometrial cancer. However, because loss of the ovaries can cause several health problems in patients, strategies for the prevention of such problems need to be established. Hence, we decided to conduct a multicenter randomized clinical trial to assess the effect of raloxifene on bone mineral density (BMD), bone metabolism, and the lipid profile of patients who had undergone surgery for patients with endometrial cancer.Materials and MethodsPatients with endometrial cancer were enrolled after treatment. The participants were randomized into 2 groups: group 1 included 39 women who received alfacalcidol (1 μg/d) alone and group 2 included 37 women who received alfacalcidol and the test drug, raloxifene hydrochloride, at a dose of 60 mg/d. The BMD of lumbar spine and femoral neck, serum bone markers, as well as lipid profile parameters were evaluated at enrollment as well as 6, 12, and 24 months after the enrollment. The primary efficacy end point was the percentage change from baseline to 24 months in lumbar spine (L2-L4) and femoral neck BMD.ResultsSixty-four women completed the 24-month study. At 24 months, the lumbar and femoral neck BMDs were significantly increased in group 2 compared with group 1 (3.5% vs −0.8% and 2.3% vs −2.8%, respectively). In group 2, low-density lipoprotein-cholesterol levels were significantly reduced by 13.6% and serum N-terminal telopeptide of type I collagen as well as bone-specific alkaline phosphatase values were significantly reduced by 16.7% and 25.7%, respectively. The patients who received adjuvant therapy for endometrial cancer showed a significantly higher response to raloxifene (5.8% vs 1.9%). Recurrence was detected in 2 (2.6%) patients in group 1. No severe adverse events were noted in any patient during the study period.ConclusionsRaloxifene exerts positive effects on BMD, bone metabolism, and lipid profile parameters and could provide an improved therapeutic option for patients with endometrial cancer.

Abstract Objective: To determine whether alfacalcidol—used in management of overt renal bone disease—may safely prevent renal bone disease when used earlier in course of renal failure. Design: Double blind, prospective, randomised, placebo controlled study. Setting: 17 nephrology centres from Belgium, France, the Netherlands, and the United Kingdom. Subjects: 176 patients aged 18–81 with mild to moderate chronic renal failure (creatinine clearance 15–50 ml/min) and with no clinical, biochemical, or radiographic evidence of bone disease. Interventions: Alfacalcidol 0.25 μg (titrated according to serum calcium concentration) or placebo given for two years. Main outcome measures: Quantitative histology of bone to assess efficacy of treatment and renal function to assess safety. Results: 132 patients had histological evidence of bone disease at start of study. Biochemical, radiographic, and histological indices of bone metabolism were similar for the 89 patients given alfacalcidol and the 87 controls given placebo. After treatment, mean serum alkaline phosphatase activity and intact parathyroid hormone concentration had increased by 13% and 126% respectively in controls but had not changed in patients given alfacalcidol (P<0.001). Hypercalcaemic episodes occurred in 10 patients given alfacalcidol (but responded to decreases in drug dose) and in three controls. Histological indices of bone turnover significantly improved in patients given alfacalcidol and significantly deteriorated in controls: among patients with abnormal bone histology before treatment, bone disease resolved in 23 (42%) of those given alfacalcidol compared with two (4%) of the controls (P<0.001). There was no difference in rate of progression of renal failure between the two groups. Conclusion: Early administration of alfacalcidol can safely and beneficially alter the natural course of renal bone disease in patients with mild to moderate renal failure. Key messages Key messages Treating such patients with alfacalcidol (up to 1 μg/day for two years) significantly improved their osteomalacia and hyperparathyroid disease Treatment had no apparent adverse effect on renal function Hypercalcaemic episodes were uncommon and readily responded to decreases in drug dose Alfacalcidol might be used more widely for patients with moderate renal failure not yet needing dialysis

Our trial was a 3-year, open-label, prospective, comparative, clinical study comparing the effects of oral alendronate (ALN), 10 mg daily, and alfacalcidol (AC), 1 microg daily, on bone mineral density (BMD), fracture events, height, back pain, safety and tolerability in 134 men with established primary osteoporosis. All men received 500 mg calcium daily. BMD was measured at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry (DXA). Spine radiographs were obtained at baseline and every 12 months thereafter, and were evaluated by a radiologist blinded to treatment assignment. At 3 years, AC-treated patients showed a significant mean increase of 3.5% in lumbar spine BMD, compared with a mean increase of 11.5% in men receiving ALN ( p<0.0001 between groups). The corresponding increases in femoral neck BMD were 2.3% and 5.8% for the AC and ALN groups, respectively ( p=0.0015 between groups). Over 3 years, new vertebral fractures occurred in 24.2% of the AC-treated patients and in 10.3% of the ALN-treated patients ( p=0.040). ALN-treated patients also had a significantly lower height loss. There were no between-group differences regarding nonvertebral fractures or changes in back pain. Both therapies were well tolerated, with a compliance rate >90%. We conclude that although AC has significant effects on BMD, ALN has greater effects on BMD and fracture efficacy.

Summary This systematic review demonstrates that vitamin D supplementation does not have a significant effect on muscle strength in vitamin D replete adults. However, a limited number of studies demonstrate an increase in proximal muscle strength in adults with vitamin D deficiency. Introduction The purpose of this study is to systematically review the evidence on the effect of vitamin D supplementation on muscle strength in adults. Methods A comprehensive systematic database search was performed. Inclusion criteria included randomised controlled trials (RCTs) involving adult human participants. All forms and doses of vitamin D supplementation with or without calcium supplementation were included compared with placebo or standard care. Outcome measures included evaluation of strength. Outcomes were compared by calculating standardised mean difference (SMD) and 95% confidence intervals. Results Of 52 identified studies, 17 RCTs involving 5,072 participants met the inclusion criteria. Meta-analysis showed no significant effect of vitamin D supplementation on grip strength (SMD −0.02, 95%CI −0.15,0.11) or proximal lower limb strength (SMD 0.1, 95%CI −0.01,0.22) in adults with 25(OH)D levels >25 nmol/L. Pooled data from two studies in vitamin D deficient participants (25(OH)D <25 nmol/L) demonstrated a large effect of vitamin D supplementation on hip muscle strength (SMD 3.52, 95%CI 2.18, 4.85). Conclusion Based on studies included in this systematic review, vitamin D supplementation does not have a significant effect on muscle strength in adults with baseline 25(OH)D >25 nmol/L. However, a limited number of studies demonstrate an increase in proximal muscle strength in adults with vitamin D deficiency.