Luca Idolazzi

Vitamin D status in patients with chronic plaque psoriasis

Background  Vitamin D could have important immunomodulatory effects in psoriasis.

Treatment of complex regional pain syndrome type I with neridronate: a randomized, double-blind, placebo-controlled study

OBJECTIVE Complex regional pain syndrome type I (CRPS-I) is a severely disabling pain syndrome for which no definite treatment has been established. The aim of this multi-centre, randomized, double-blind placebo-controlled trial was to test the efficacy of the amino-bisphosphonate neridronate in patients with CRP-I. METHODS Eighty-two patients with CRP-I at either hand or foot were randomly assigned to i.v. infusion of 100 mg neridronate given four times over 10 days or placebo. After 50 days the former placebo patients were given open label the same regimen of neridronate. RESULTS Within the first 20 days, visual analogue scale (VAS) score decreased significantly more in the neridronate group. In the following 20 days, VAS remained unchanged in the placebo group and further decreased in the active group by 46.5 mm (95% CI -52.5, -40.5) vs 22.6 mm (95% CI -28.8, -16.3) for placebo group (P < 0.0001). Significant improvements vs placebo were observed also for a number of other indices of pain and quality of life. During the open-extension phase in the formerly placebo group the results of treatment were superimposable on those seen during the blind phase in the active group. A year later none of the patients was referring symptoms linked to CRPS-I. CONCLUSION In patients with acute CRPS-I, four i.v. infusions of neridronate 100 mg are associated with clinically relevant and persistent benefits. These results provide conclusive evidence that the use of bisphosphonates, at appropriate doses, is the treatment of choice for CRPS-I. TRIAL REGISTRATION EU Clinical Trials Register, https://www.clinicaltrialsregister.eu/, 2007-003372-18.

Sclerostin and DKK1 in postmenopausal osteoporosis treated with denosumab

The bone mass benefits of antiresorbers in postmenopausal osteoporosis are limited by the rapid coupling of decreasing bone resorption with bone formation. Wnt signaling is involved in this coupling process during treatment with bisphosphonates, whereas its role during treatment with the anti‐receptor activator of NF‐κB ligand (RANKL) antibody denosumab is unknown. The study population includes patients participating in a placebo‐controlled trial lasting 36 months: 19 women were on placebo and 24 on subcutaneous 60 mg denosumab every 6 months. All measured parameters (serum C‐terminal telopeptide of type I collagen [sCTX], serum bone alkaline phosphatase [bAP], Dickkopf‐1 [DKK1], and sclerostin) remained unchanged during the observation period in the placebo group. sCTX and bAP were significantly suppressed by denosumab treatment over the entire follow‐up. Denosumab treatment was associated with significant (p < 0.05) increases (28% to 32%) in serum sclerostin over the entire study follow‐up. Serum DKK1 significantly decreased within the first 6 months with a trend for further continuous decreases, which reached statistical significance (p < 0.05) versus placebo group from the 18th month onward. The changes in DKK1 were significantly and positively related with the changes in sCTX and bAP and negatively with hip bone mineral density (BMD) changes. The changes in sclerostin were significantly and negatively related only with those of bAP. The changes in bone turnover markers associated with denosumab treatment of postmenopausal osteoporosis is associated with significant increase in sclerostin similar to those seen after long‐term treatment with bisphosphonates and significant decrease in DKK1. This latter observation might explain the continuous increase over 5 years in BMD observed during treatment of postmenopausal osteoporosis with denosumab.

The waning of teriparatide effect on bone formation markers in postmenopausal osteoporosis is associated with increasing serum levels of DKK1.

CONTEXT The effect of teriparatide (TPD) on bone turnover is initially exuberant but then diminishes. TPD is thought to stimulate bone formation by down-regulating the expression of specific Wnt antagonists, such as of sclerostin and Dickkopf-1 (DKK1). OBJECTIVE Our objective was to determine whether long-term treatment with TPD is associated with increasing serum levels of either sclerostin or DKK1. DESIGN AND SETTING Ancillary observation was made of patients participating in a randomized clinical trial. PATIENTS, INTERVENTION, AND OUTCOMES: Fifty-five women with postmenopausal osteoporosis were randomly allocated to treatment for 18 months with either TPD 20 μg daily or placebo. RESULTS In the TPD group, both N-propeptide of type I collagen and C-terminal telopeptide of type I collagen rose significantly by 108 and 175% within the first 6 months. At month 18, the mean values decreased significantly compared with month 12 (-10 and -12%, respectively), but they were still significantly higher than baseline (+84 and 152%, respectively). Sclerostin remained stable over the entire study period in both groups. DKK1 did not change during the first 6 month of treatment, but only in the active group, it rose significantly at month 12 (median change +26.9%) and remained elevated at month 18 (+29.7%), at the time when the pharmacological effect of treatment with TPD appeared to be declining. CONCLUSION Long-term (>12 months) treatment with TPD is associated with an increase in serum levels of DKK1 that might be associated with the appearance of declining effect on bone formation markers.

Bisphosphonate treatment of postmenopausal osteoporosis is associated with a dose dependent increase in serum sclerostin.

The benefits coming from long-term treatment of postmenopausal osteoporosis with bisphophonates are limited by a coupled decrease in bone formation. The objective of this study is to determine whether this decrease in bone formation is associated with changes in serum levels of the WNT signaling antagonist sclerostin or Dickkopf-1 (DKK1). This is an ancillary observation from patients participating in a 12 months, phase 2, randomized clinical trial. We analyzed 107 patients given either monthly intramuscular neridronate (12.5, 25 or 50 mg) or placebo. Serum C-terminal telopeptide of type I collagen (sCTX, a bone-resorption marker) decreased by 61%, 75% and 73% in the 12.5, 25 and 50 mg dose groups, respectively. Mean changes in bone alkaline phosphatase (bAP) at 12 months were -47%, -60.0% and -52.6% in the groups receiving 12.5, 25 or 50 mg neridronate, respectively. Serum DKK1 remained unchanged at all time points in the 3 groups. Serum sclerostin increased versus placebo group gradually and significantly only in patients treated with 25 or 50 mg neridronate monthly, reaching 138-148% of baseline values (P<0.001). Changes in serum sclerostin at 12 months were negatively correlated with changes in bAP (P<0.001) even when data were adjusted for sCTX changes and only treated patients were included. In conclusions, decreased bone formation after several months of bisphosphonate therapy is associated with increased serum levels of sclerostin. This might suggest that Wnt signaling may play a role in the coupling between resorption and formation.

Short-Term Effects on Bone Turnover Markers of a Single High Dose of Oral Vitamin D3

CONTEXT Vitamin D deficiency is often treated or prevented by high intermittent doses of vitamin D to achieve a better treatment adherence, but treatment outcomes were contradictory, and even a transient increase in fracture and fall risk was reported. OBJECTIVE The objective of the study was to investigate the short-term effects on bone turnover markers of a single bolus of vitamin D₃. DESIGN, SETTING, PATIENTS, AND INTERVENTION Twelve elderly subjects (eight women, four men; mean age 76 ± 3 yr) were given a single oral bolus of 600,000 IU vitamin D₃. Blood samples were taken at baseline and 1, 3, 7, 14, 30, 60, and 90 d after vitamin D₃ administration. Twenty-four subjects served as controls. MAIN OUTCOME MEASURES Changes in serum levels of 25-hydroxyvitamin D (25OHD), 1,25-dihydroxyvitamin D, PTH, C-terminal-telopeptides of type I collagen, cross-linked N-telopeptide of type I collagen (sNTX), osteocalcin, and bone-specific alkaline phosphatase. RESULTS No relevant changes in 25OHD and bone turnover markers were observed in the controls. In treated subjects, serum 25OHD attained a peak increment to 67.1 ± 17.1 ng/ml (P < 0.001) at d 3. Subsequently it slowly decreased to 35.2 ± 5.8 ng/ml (P <0.01 vs. a baseline value of 21.7 ± 5.6 ng/ml). Mean serum PTH concentration decreased by 25-50% and serum 1,25-dihydroxyvitamin D rose by 25-50%. Serum CTX and sNTX rose significantly at d 1 (P < 0.01), they attained a peak increment greater than 50% at d 3, and they subsequently decreased almost back to baseline values at d 90. Serum osteocalcin slightly rose within the first 3 d and then declined by d 60. No changes were observed in serum bone-specific alkaline phosphatase. CONCLUSIONS Our results indicate that the use of large doses of vitamin D may be associated with acute increases in C-terminal-telopeptides of type I collagen and sNTX, which may explain the negative clinical results obtained by using intermittent high doses of vitamin D to treat or prevent vitamin D deficiency.

Bone Involvement and Osteoporosis in Mastocytosis

Bone involvement is frequent in patients with systemic mastocytosis. Osteoporosis is the most prevalent bone manifestation, but diffuse osteosclerosis or focal osteolytic or osteosclerotic lesions are not infrequent. The risk of osteoporotic fractures is high, especially at the spine and in men. Routine measurements of bone mineral density and vertebral morphometry are warranted. The bone turnover markers indicate the involvement of complex bone metabolism in mastocytosis-related manifestations. Bisphosphonates represent the first-line treatment for osteoporosis-related mastocytosis.

Bisphosphonates vs infliximab in ankylosing spondylitis treatment

OBJECTIVE The objective of this study was to evaluate if the anti-inflammatory properties of bisphosphonates and their effect on bone turnover could be useful in the treatment of AS. METHODS Sixty patients were consecutively assigned in a 1:1 ratio in a 6-month open-label, single-centre study on active AS to receive monthly i.v. neridronate (100 mg) or standard infliximab (5 mg/kg) therapy. RESULTS A significant reduction in the mean BASDAI was observed over 6 months of either neridronate (-1.72) or infliximab (-1.62) administration. The BASFI decreased significantly at 3 and 6 months in the neridronate arm, while in the infliximab group a significant reduction at 3 months but not 6 months was observed. The 10-cm visual analogue scale for axial pain decreased significantly and comparably at 3 and 6 months in both groups. No significant differences between treatment arms for all these changes were observed at both 3 months and the final assessment. The BASMI was not significantly modified in the neridronate or infliximab group. No significant variations of BMD were observed in the infliximab group, while in patients treated with neridronate a significant increase was observed at the lumbar spine. CONCLUSION High i.v. doses of the amino-bisphosphonate neridronate are as effective as infliximab therapy in reducing disease activity in AS patients, with additional benefits on BMD changes. Further studies to confirm these results over a longer time frame are warranted together with the possibility to explore the long-term efficacy of a combination of lower anti-TNF doses with bisphosphonates.

Prevalence, pathogenesis, and treatment options for mastocytosis-related osteoporosis

Mastocytosis is a rare condition characterized by abnormal mast cell proliferation and a broad spectrum of manifestations, including various organs and tissues. Osteoporosis is one of the most frequent manifestations of systemic mastocytosis, particularly in adults. Osteoporosis secondary to systemic mastocytosis is a cause of unexplained low bone mineral density that should be investigated when accompanied by suspicious clinical elements. Bone involvement is often complicated by a high recurrence of fragility fractures, mainly vertebral, leading to severe disability. The mechanism of bone loss is the result of different pathways, not yet fully discovered. The main actor is the osteoclast with a relative or absolute predominance of bone resorption. Among the stimuli that drive osteoclast activity, the most important one seems to be the RANK-RANKL signaling, but also histamine and other cytokines play a significant role in the process. The central role of osteoclasts made bisphosphonates, as anti-resorptive drugs, the most rational treatment for bone involvement in systemic mastocytosis. There are a few small studies supporting this approach, with large heterogeneity of drug and administration scheme. Currently, zoledronate has the best evidence in terms of gain in bone mineral density and bone turnover suppression, two surrogate markers of anti-fracture efficacy.

Zoledronic Acid in Osteoporosis Secondary to Mastocytosis

BACKGROUND Osteoporosis is the prevalent manifestation of bone involvement in patients with systemic mastocytosis. Mastocytosis-related osteoporosis is characterized by both absolute and relative prevalence of osteoclastic activity, consistent with the positive results reported in small series of patients with antiresorptive drugs, such as bisphosphonates. The aim of this study is to investigate the efficacy of zoledronic acid in patients with mastocytosis-related osteoporosis. METHODS Twenty-five patients with osteoporosis secondary to indolent systemic mastocytosis were given a single intravenous infusion of 5 mg zoledronic acid dissolved in 100 mL of 0.9% saline over 60 minutes. RESULTS After 1 year, the mean increase in bone mineral density was 6.0% ± 4.4% at the spine and 2.4% ± 3.2% at the total hip. Serum levels of bone turnover markers decreased versus baseline: bone alkaline phosphatase -34% and -35%, and C-terminal telopeptide -68% and -56% at 6 and 12 months, respectively. None of the patients reported new fractures during the year of follow-up. In all the first 20 treated patients, a transitory acute phase response was observed, but this was prevented in 4 of 5 subsequent patients in whom acetaminophen was given systematically during the 3 days post-infusion. CONCLUSIONS A single 5 mg zoledronic acid intravenous infusion in patients with osteoporosis secondary to indolent systemic mastocytosis is associated with significant increases in spine and hip bone mineral density and decreases of bone turnover markers over at least 1 year. Yearly zoledronic acid might represent a therapeutic option for indolent systemic mastocytosis-associated osteoporosis.