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Objective: The duration of treatment with glucocorticoids (GC) in polymyalgia rheumatica (PMR) is often longterm. Amino bisphosphonates (N-BP) are used in PMR for the prevention of GC-induced osteoporosis, but they coulsd also have immunomodulatory properties. Whether they can be effective as an adjuvant treatment in PMR is unknown. We aimed to establish whether the use of N-BP in our PMR cohort may be associated with GC discontinuation., Methods: We conducted a retrospective review of all patients diagnosed with PMR recorded in our electronic medical notes. Cox regression analyses were used to examine the association between the use of N-BP and discontinuation of GC., Results: Data were retrieved for 385 patients (mean age 71 ± 10 yrs, 64% females, mean initial prednisone dose 19 ± 9 mg/day). The median followup time was 38 months (range 9-57); more than 60% of patients were exposed to N-BP. GC were discontinued in 47% of patients after a median time of 20 months (range 14-27), but subsequently restarted in 39%. Overall, 276/385 patients (72%) were actively treated at their last available evaluation (mean prednisone dose 4.9 ± 5.5 mg/day), while 123/205 (60%) were still receiving GC after 24 months of followup. The use of N-BP was associated with the discontinuation of GC (adjusted HR 0.66, 95% CI 0.50-0.88), independent of age, initial GC dose, and osteoporosis., Conclusion: Unlike current guidelines, longterm treatment with GC is often necessary. These preliminary data suggest that N-BP may be involved in the management of PMR.

Aim of this study was to evaluate the efficacy and tolerability of intra-articular (IA) clodronate, compared to saline solution, in patients with symptomatic knee osteoarthritis (KOA). In this double-blind phase 3 randomized clinical trial, patients were randomized to receive once weekly IA injection of 2 mg clodronate or placebo for 4 weeks with 12 weeks of follow-up. The primary objective was the sum of spontaneous, on passive movement, and at digital pressing pain relief assessed by visual analogue score (VAS) of 0-100 at 5 weeks after the final injection. Improving in Western Ontario MacMaster (WOMAC) scale, Lequesne index, consumption of acetaminophen, and physician or patient overall judgment were secondary objectives. Study population included 80 patients, 67 women and 13 men aged 66 ± 6 (SD) years. A significant improvement for all efficacy parameters was observed at all-time points in both groups. A significant difference in favor to clodronate in VAS for pain was observed 5 weeks after the last injection (-114.6 vs. -87.2 for clodronate and placebo group, respectively; p < 0.05). The improvements in Lequesne index, global KOA evaluation from both patients and investigators, and the WOMAC pain subscale were significantly greater in the clodronate group. The proportion of patients that did not require acetaminophen was significantly greater in the clodronate group (about 10 vs. 30 % for clodronate and placebo group, respectively; p < 0.05). IA 2 mg clodronate is associated with small and transient symptomatic and functional benefits and it is safe in KOA patients.

The coupling of bone formation to bone resorption during treatment of postmenopausal osteoporosis with antiresorbers might be related to changes in Wnt/b-catenin signaling. We compared the effects of two bisphosphonate treatments on two Wnt-inhibitors Sclerostin (SOST) and Dickkopf-related protein 1 (DKK1). The study population included 74 women with postmenopausal osteoporosis participating simultaneously in two multicenter, placebo controlled trials. The patients were randomized to: intramuscular clodronate 100mg/week (CLO) (N=36), and yearly intravenous therapy with 5mg zoledronate (ZOL) (N=18) and placebo (N=20). Bone turnover markers (intact N-propeptide of type I collagen [P1NP], C-terminal telopeptide of type I collagen [CTX]) remained unchanged in the placebo group while they significantly decreased during treatment with the two bisphosphonates, versus both placebo and baseline. In CLO treated patients serum DKK1 remained stable over the entire period of observation while serum SOST levels increased significantly after 12months of treatment both versus placebo group (p<0,005), baseline (p<0,001) and ZOL treated group. In the ZOL group, DKK1 levels increased significantly within one month and for the following 6months and it fell back to baseline values at 12months. The second ZOL infusion was again associated with an increase in DKK1 a month later, although to a lesser extent. In conclusion, in this study we have found that the treatment of postmenopausal osteoporosis with intermittent yearly ZOL is associated with transient and declining increases in DKK1 while continuous treatment with CLO, results in a late increase in serum SOST. These preliminary results and further ad hoc studies might contribute to shed light on our understanding of the bone coupling effects taking place during treatment of osteoporosis with different anti-resorbers or with different treatment regimens., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Osteogenesis imperfecta (OI) is a hereditary disease characterized by low bone mass, increased bone fragility, short stature, and skeletal deformities. This study focuses on OI type I, the mildest form of the disease. Bisphosphonates represent the prevailing standard of care in patients with OI. Teriparatide (TPD) is a PTH analog with bone-anabolic actions which has been approved for osteoporosis treatment. Thirteen postmenopausal women with type I OI who had been on treatment with neridronate for at least 2 years and who incurred new vertebral fracture during treatment were treated with TPD for 18 months. Bone mineral density (BMD) increased significantly over 18 months up to 3.5 % at the lumbar spine (p = 0.001), while no significant changes were noted in hip BMD. Serum markers of bone formation and of bone resorption increased significantly during the treatment. The Wnt inhibitors serum dickkopf-1 (DKK1) and sclerostin were also measured. A nonsignificant increase was seen in serum sclerostin levels, while serum DKK1 rose gradually and significantly during TPD treatment. In patients affected by type I OI, TPD treatment is associated with a remarkable response in markers of bone formation. This suggests a normal osteoblastic response to TPD. However, the observed increases in BMD were somewhat lower than those in postmenopausal or senile osteoporosis treated with TPD for the same lag time. Our results open the possibility to develop TPD for the treatment of adult type I OI, but particularly for the lack of a control group, a properly designed controlled study is warranted.

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.

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., (Copyright © 2012 American Society for Bone and Mineral Research.)

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.

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The use of intravenous nitrogen-containing bisphosphonates (N-BPs) is associated with the appearance of an acute phase response (APR) in a proportion of the patients for reasons that are poorly understood. The APR was attributed to the indirect activation of γδ T cells with the release of interferon-γ and tumor necrosis factor (TNF). Forty patients with postmenopausal or senile osteoporosis (age range = 53-91 years) never previously treated with intravenous (i.v.) bisphosphonate, received a single 5-mg zoledronic acid (ZOL) iv infusion over 15 minutes. White blood cells were counted and analyzed with an automated hematology analyzer (ADVIA 2120i Siemens, New York, USA) and by flow cytometer (BD FACSCanto, Becton Dickinson). The occurrence of APR was defined by the occurrence of fever (>37 °C) during the next 2 days. Forty-two percent of patients (17 of 40) receiving the infusion of ZOL experienced an APR. Compared with the others they were younger (69 ± 7 years versus 74 ± 8 years; p = 0.06), and both the proportion and absolute number of γδ T cells were significant higher (p = 0.02 and p = 0.013, respectively). Nonsignificant differences were found between the two groups for white blood cells and for the other circulating lymphocyte subpopulations. Age was inversely correlated with circulating γδ T cells (p = 0.003) but the difference between the two groups in circulating γδ T cells persisted for age-adjusted values and vice versa. In conclusion, the results of this study indicate that the number of circulating γδ T cells, together with age, are important determinant of the occurrence of APR after intravenous infusion of ZOL and possibly of any other N-BPs., (Copyright © 2012 American Society for Bone and Mineral Research.)

In patients with primary hyperparathyroidism (PHPT) not suitable for surgical correction, a skeletal protection with bisphosphonates is considered a reasonable option, but the long-term effects after treatment discontinuation are not well known. Sixty postmenopausal women with PHPT were given 400-600 IU vitamin D(3) daily and 100 mg neridronate IV every 2 months for 2 years with 2 additional years of follow-up without antiresorptive therapies. Bone mineral density (BMD) progressively rose by 6.7 ± 7.6% (SD) and by 2.9 ± 4.5% at the spine and femoral neck, respectively. During follow-up, mean BMD progressively fell, but after 2 years it was still 3.9 ± 5.5% higher than baseline values at the spine. Bone alkaline phosphatase and serum C-telopeptide of type I collagen decreased significantly within 6 months (28 and 49% versus baseline, respectively) and rose to baseline values within 6-12 months during follow-up. Serum PTH significantly rose from baseline during treatment, but it remained significantly higher than baseline during follow-up. The PTH changes were significantly correlated with serum 25-hydroxyvitamin D (25OHD) levels. In conclusion, in this study we observed that in patients with mild PHPT treatment with bisphosphonates is associated with the expected changes in bone-turnover markers and that the significant increases of both hip and spine BMD are partially maintained for at least 2 years after treatment discontinuation at the vertebral site. The marked increases in serum PTH levels, particularly in subjects with low 25OHD levels, persist after treatment discontinuation and this raises the suspicion that this might reflect a worsening of PHPT.

Vitamin D plays a crucial role for the prevention and treatment of both postmenopausal and senile osteoporosis and possibly for a number of other conditions. The prevalence of vitamin D deficiency remains extremely high among elderly subjects. This indicates that both the perception of the problem and the interventions so far implemented remain inadequate. This is further complicated by the observation that the lower normal range of 25-hydroxycholecalciferol (calcidiol) and the minimum daily allowance of vitamin D have been recently set to values considerably higher. The association of calcidiol with the specific osteoporosis treatment, for example associating the two therapies on one specific day (once weekly) is an efficient way for increasing compliance and effectiveness of the osteoporosis therapy. The weekly dose of calcidiol may be adapted to individual needs, i.e 4,000 to 6,000 IU (or 20-30 drops) according to age or risk factors for vitamin D deficiency.

Vitamin D deficiency is a relevant problem particularly in south Europe and in over 65 year old subjects, that is often underestimated. Vitamin D deficiency represents a real medical emergency also for its role in the patho-physiology of muscular-skeletal diseases. Chronic vitamin D deficiency leads to severe bone and muscular outcomes including: osteoporosis, osteomalacia and proximal limb myopathy. These increase the risk of falling and fractures. The efficacy of vitamin D treatment in decreasing the fracture risk has been reporting in several studies. The negative results of some recent studies questioned the clinical vitamin D efficacy. However these studies have a number of methodological problems and even the interpretation of the results is questionable. In this paper we review all these aspects. This analysis permits to confirm that vitamin D treatment can be extremely cost-effective when given to people at high risk of deficiency. An acceptable compliance is obviously of critical importance.