Denosumab for the Treatment of Mastocytosis-Related Osteoporosis: A Case Series.

The purpose of this study was to investigate the therapeutic effect of denosumab, an anti-RANKL monoclonal antibody for the treatment of bone loss in indolent systemic mastocytosis (ISM) patients intolerant to bisphosphonates. Four patients underwent upon informed consent a treatment with denosumab 60 mg administered subcutaneously every 6 months with the same regimen used for postmenopausal osteoporosis. Bone mineral density (BMD) was measured at lumbar and femoral sites at baseline and after 1 year. C-terminal telopeptide of collagen type I (CTX), bone alkaline phosphatase (bALP) and tryptase serum level were determined at baseline and after 12 months with fasting blood samples withdrawals. BMD increased significantly at both sites during the 12 months; all the patients had an important decrease of serum CTX and of lesser extent of bALP serum levels. After denosumab treatment, a decrease in serum tryptase level was observed in all the patients. No adverse events or new fractures occurred. Denosumab seems to be a valid alternative for the treatment of bone loss in ISM. RANKL might be of key importance in the pathogenesis of ISM bone involvement.

Dickkopf-1 and sclerostin serum levels in patients with systemic mastocytosis.

Bone involvement, mainly osteoporosis but also osteosclerosis, is frequent in patients with indolent systemic mastocytosis (ISM). The recent characterization of the canonical Wnt/ß-catenin pathway in the regulation of bone remodeling provided important insights for our understanding of the pathophysiology of a number of conditions. The regulation of Wnt pathway in bone is predominantly driven by the production of receptor inhibitors such as Dickkopf-1 (DKK1) and sclerostin (SOST). This study aimed to explore if the various bone involvements in patients with ISM might be explained by variations in serum levels of DKK1 and SOST. This is a cross-sectional study in an adult ISM cohort (13 men and 13 women with diagnosed ISM) and fifty-two healthy sex and age-matched controls. Early morning, fasting and venous sampling was obtained in all subjects. The main outcome measures were serum bone-specific alkaline phosphatase (bALP), C-terminal telopeptides of type I collagene (CTX), DKK1, SOST, parathyroid hormone (PTH), bone mineral density, and prevalent vertebral fractures. Mean DKK1 serum levels were about two-folds higher in patients, than in controls (65,0 ± 43.3 vs. 33.1 ± 19.4 pmol/L, respectively; p < 0.001), irrespective of the presence of osteoporotic or diffuse osteosclerotic bone involvement. DKK1 serum levels were positively correlated with PTH and both CTX and bALP. Mean SOST serum levels were not significantly different in patients versus controls, and we did not observe any significant correlation between SOST and any available clinical or laboratory parameters, with the only exception of a positive correlation with age. In conclusion, in our study, we observed that DKK1, but not SOST, serum levels significantly increased in ISM patients with various bone involvements, and correlated with PTH and bone turnover markers. Our results suggest that the Wnt/ß-catenin pathway is not primarily involved in the pathophysiology of the array of bone involvement in ISM.

Acute phase response after zoledronic acid is associated with long-term effects on white blood cells.

We have recently reported a long-lasting decrease in circulating γδ T cells in osteoporotic patients on oral amino-bisphosphonates (N-BPs). Here we verify whether these changes are associated with the occurrence of acute phase response (APR) to intravenous (IV) zoledronic acid (ZOL) or changes of other circulating white blood cells (WBC). WBC count was obtained before and 1 year after a single IV administration of 5 mg ZOL in 36 osteoporotic patients (mean age 72 ± 9, range 45-86 years) without other relevant diseases; 12 of 36 patients developed the classical APR. After 1 year in the patients who experienced an APR, but not in the others, a significant decrease not only of γδ T cells (-30 %), but also of total lymphocytes (-11 %) and eosinophils (-27 %), was observed. The mechanism leading to the observed decrease of circulating lymphocytes and eosinophils remains unclear, but our observation opens a new frontier for the understanding of the immunoeffects of N-BPs.

Long-term effects of amino-bisphosphonates on circulating γδ T cells.

The aim of this study was to explore whether desensitization to the occurrence of the acute-phase response (APR) in patients previously treated with amino-bisphosphonates (N-BPs) is due to a long-lasting reduction in the number of circulating γδ T cells. Circulating lymphocyte subpopulation counts were obtained from 63 patients with postmenopausal or senile osteoporosis at baseline and after 2 days and 12 months of the first intravenous (IV) 5 mg zoledronic acid (ZOL) infusion. At baseline both the proportion and absolute number of circulating γδ T cells were significantly higher in patients who had never used N-BPs vs. previous users, either oral or IV. A typical APR was observed in none of the patients given IV ZOL a year earlier, in 6 (22 %) of the patients previously treated with oral N-BPs, and in 13 (57 %) of the patients naive to any N-BP treatment. In patients naive to N-BPs, a significant reduction in both total lymphocytes and their subsets was observed 2 days after ZOL infusion; all these changes returned to baseline values 1 year later with the exception of γδ T cells, which remained significantly lower in terms of both proportion and absolute number. These results indicate for the first time that both IV and oral N-BP treatments are associated with a long-lasting decrease in circulating γδ T cells, and this may explain the lower incidence of APR in patients previously exposed to N-BPs. Other clinical implications of this sustained effect of N-BPs on immune-regulatory cells might be important.

Circulating Dickkopf-1 and sclerostin in patients with Paget's disease of bone.

Paget disease of bone is a chronic metabolic bone disorder characterized by increased bone resorption and new bone formation. The aim of this study is defining the role of inhibitors of canonical Wnt/b-catenin signaling pathway in patients with Paget disease of bone. Scarce and contrasting results have been reported in literature. We studied 40 patients (15 females and 25 males) with radiological and scintigraphic evidence of Paget disease of bone and 40 healthy subjects matched by age and sex. N-propeptide of type I collagen, C-terminal telopeptide of type I collagen, sclerostin, and Dickkopf-related protein 1 (DKK1) were evaluated by blood samples in our laboratory. As expected, mean serum levels of bone turnover markers (N-propeptide of type I collagen and C-terminal telopeptide of type I collagen) were significantly higher in the Paget disease of bone group compared with the control group. No difference was observed between groups in Dickkopf-1 and sclerostin. Dickkopf-1 and sclerostin were never correlated with each other or with bone turnover markers. Sclerostin was positively correlated with age. In conclusion, our results suggest that the regulators of the Wnt-ß catenin pathway are not altered in patients with Paget disease of bone. The positive correlation we found between sclerostin and age in Paget disease of bone patients indicates that in comparative studies, sclerostin serum levels must be adjusted for age.

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.

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.