Long-term denosumab treatment restores cortical bone loss and reduces fracture risk at the forearm and humerus: analyses from the FREEDOM Extension cross-over group.

Upper limb fractures (including wrist, forearm, and humerus) represent a significant burden among postmenopausal women with osteoporosis. Up to 7 years of treatment with denosumab resulted in an increase in bone mineral density and decrease in fractures in upper limb sites. INTRODUCTION: Upper limb (wrist, forearm, and humerus) fractures are a significant burden in osteoporosis, associated with significant morbidity and mortality. Denosumab, a monoclonal antibody against RANK ligand, increases bone mineral density (BMD) and decreases vertebral, nonvertebral, and hip fractures. Here, we evaluated the long-term effect of denosumab treatment on upper limb fracture risk and BMD. METHODS: In the FREEDOM trial, subjects were randomized 1:1 to receive every-6-month denosumab 60 mg or placebo subcutaneously for 3 years, after which all subjects could receive denosumab for up to 7 years (Extension). Among placebo subjects who completed FREEDOM and enrolled in the Extension, wrist, forearm, humerus, and upper limb fracture rates and rate ratios between different time periods (FREEDOM years 1-3, Extension years 1-3, and Extension years 4-7) were computed. BMD at the ultradistal radius, 1/3 radius, and total radius was analyzed in a subset of subjects in a BMD substudy. RESULTS: This analysis included 2207 subjects (116 in the BMD substudy). Fracture rates decreased over the 7-year Extension; fracture rate ratios between Extension years 4-7 (denosumab) and FREEDOM years 1-3 (placebo) reduced significantly for the wrist (0.57), forearm (0.57), humerus (0.42), and upper limb (0.52; p < 0.05 for all). Percentage increase in BMD from Extension baseline at the ultradistal radius, 1/3 radius, and total radius was significant by Extension year 7 (p < 0.05 for all). CONCLUSIONS: Long-term treatment with denosumab decreases upper limb fracture risk and increases forearm BMD, suggesting beneficial effects on both cortical and trabecular bone accruing over time.

Evaluation of the efficacy, safety and pharmacokinetic profile of oral recombinant human parathyroid hormone [rhPTH(1-31)NH(2)] in postmenopausal women with osteoporosis.

CONTEXT: Treatment of osteoporosis with subcutaneous (SC) injections of rhPTH(1-34) or rhPTH(1-84) is associated with significant improvements in BMD and reductions in osteoporotic fractures. However, subcutaneous injections can be associated with discomfort and thus deteriorating compliance. OBJECTIVE: The UGL-OR1001 trial aimed to establish the efficacy and safety parameters of a novel oral tablet formulation of rhPTH(1-31)NH(2) and matching placebo tablets and open-label teriparatide positive control in postmenopausal women with osteoporosis. DESIGN: 24 weeks of randomized, double-blind treatment with once daily doses of 5mg oral treatment or corresponding placebo, or open-label subcutaneous teriparatide. PATIENTS OR OTHER PARTICIPANTS: Women diagnosed with postmenopausal osteoporosis as detected by lumbar spine DXA, with an exclusion of those with prior treatment with bone active agents. INTERVENTION(S): Orally formulated recombinant human PTH(1-31)NH(2) and placebo, or open-label subcutaneous teriparatide as a positive control. MAIN OUTCOME MEASURE(S): The primary endpoint was to characterize the percent change from baseline in bone mineral density (BMD) at L1-L4 axial lumbar spine after 24 weeks in the rhPTH(1-31)NH(2) arm. Secondary and exploratory endpoints included safety and tolerability of the oral formulation, measurement of biochemical markers of bone turnover, and evaluation of the PK profile at first and last dose. The study was registered at ClinicalTrials.gov with the identifier: NCT01321723. RESULTS: The oral tablet formulation of rhPTH(1-31)NH(2) resulted in similar PK profiles at both timepoints with mean C(max) values similar to subcutaneous administration. In the rhPTH(1-31)NH(2) arm, a 2.2% increase in lumbar spine BMD was observed compared to baseline (p<0.001), while no change was observed in the placebo arm. Open-label teriparatide resulted in a 5.1% increase in LS BMD (p<0.001). In the oral PTH study arm, the bone formation marker osteocalcin was increased by 32%, 21% and 23% at Weeks 4, 12 and 24, respectively. There was no significant increase in the level of the bone resorption marker CTx-1. CONCLUSIONS: In summary, these data demonstrate that enteric-coated oral tablet formulation technology consistently generated robust levels of exposure of rhPTH(1-31)NH(2) leading to induction of bone formation without inducing bone resorption resulting in significantly increased levels of LS BMD. Few adverse events were observed, recommending this orally delivered drug candidate for further development.

A working classification of scleroderma spectrum disorders: a proposal and the results of testing on a sample of patients.

OBJECTIVE: To propose a working classification for scleroderma spectrum disorders (SDS), based on criteria shown in the past to be specific for the condition: sclerodermatous skin involvement, specific autoantibodies and specific microvascular abnormalities, to obtain mutually exclusive subgroups of SDS and to test this classification on a sample of patients. This is an attempt to improve the current classifications used in research studies, which are all based on the extent of skin involvement only. METHODS: Patients (n= 165) referred to the Microvascular Laboratory of the Division of Rheumatology between 1976 and 1992, who had participated in various other studies in the Division and for whom therefore systematically collected clinical and laboratory data were available. Evaluation of skin involvement, clinical, laboratory, and microvascular studies were performed independently and a subgroup assignment was made "blindly" from coded data. RESULTS: Results demonstrated that significant differences were present between our subgroups of SDS with regard to meaningful variables. Comparisons of our results with previously used classifications such as the ACR preliminary criteria study and later subsets used by more recent investigators, demonstrated that our classification permitted us to include less severe cases than those meeting ACR criteria. CONCLUSION: Our results show that by dividing SDS into groups using the cutaneous, microvascular and autoantibody characteristics, while using well-defined criteria and inclusion-exclusion rules to obtain mutually exclusive subgroups, can reveal differences that may otherwise be masked. This study has suggested new avenues of research. A replication study should be performed with a systematic follow-up. This is a working classification, i.e. it can be modified as new findings using updated technology become available. The focus should be on clearly defining criteria for classification and collected data. Then between-center comparisons will be possible.

Evaluation of treatment efficacy of Raynaud phenomenon by digital blood pressure response to cooling. Raynaud's Treatment Study Investigators.

Our previous studies have suggested that digital blood pressure response to cooling could provide a measure of the efficacy of treatments that are administered to patients with Raynaud phenomenon (RP). This method was used on 158 primary RP patients participating in a multicenter, randomized clinical trial that compared the efficacy of sustained-release nifedipine with temperature biofeedback in the treatment of RP. A pill placebo and electromyography served as controls. The response to local finger cooling was measured at 30 degrees, 20 degrees, 15 degrees and 10 degrees C in a temperature-controlled room under standardized conditions. The results showed that, at the 15 degrees C and 10 degrees C local cooling temperatures, the patients in the nifedipine group had a higher mean digital systolic blood pressure, a higher relative digital systolic blood pressure (RDSP), a smaller proportion of subjects with RDSP < 70% and a smaller proportion of subjects with a zero reopening pressure than the patients in the three other treatment groups. These results were statistically significant at 10 degrees C, the nifedipine group being significantly different from all others (p < 0.05); no significant difference was found between the three other treatment groups.

Association between cigarette and alcohol consumption and Raynaud's phenomenon.

The association between alcohol and cigarette consumption and Raynaud's Phenomenon (RP) was examined by using data from an American-French collaborative, cross-sectional, epidemiological study in five geographically varied regions (Charleston, South Carolina, USA; and Grenoble, Tarentaise, Nyons, and Toulon, France). Using logistic regression models that take into account the sampling weights, the association was examined stratified by gender and adjusted for age, body mass index, self-perceived health, and education. Overall, neither cigarette nor alcohol consumption showed a significant association with RP. In men, however, a V-shaped relationship between drinking and RP was observed, with mild consumption (1 to 7 drinks per week) exhibiting a protective effect over abstinence, whereas occasional (less than 1 drink per week), moderate (8 to 18 drinks per week) and heavy consumption (more than 18 drinks per week) did not. Among the participants with RP, no significant association was observed between RP attack frequencies and the amount of either alcohol or cigarette consumption. These negative findings suggest that having RP is not strongly affected by alcohol or cigarette consumption.

An objective method to estimate the severity of Raynaud phenomenon: digital blood pressure response to cooling.

The treatment efficacy of patients with Raynaud phenomenon (RP) is determined from the decrease in severity of this condition, usually based on a decrease in frequency of RP attacks as reported by patients in a diary. Although subjective, this method is still the main endpoint measure in clinical trials. The results of patients' digital blood pressure responses to cooling were compared with the reported RP attack frequency to determine whether the former could be used to estimate the severity of RP. The effect of local finger cooling on the digital systolic blood pressure was tested at 30 degrees C, 20 degrees C, 15 degrees C and 10 degrees C on 136 subjects with RP. The RP attack frequency was dichotomized into daily versus less than daily attacks. The frequency of attacks and the digital systolic pressure (DSP) showed a significant association at all cooling temperatures (those with daily attacks showed lower DSP than those with less frequent attacks). In addition, patients experiencing daily attacks of RP showed a zero reopening pressure at higher local temperatures than those with less frequent RP attacks. These results demonstrate that the response of the digital systolic blood pressure to cooling is closely associated with the RP attack frequency and therefore can be considered as an objective estimate of RP severity. This physiological measurement should be most useful in evaluating the clinical course of RP and the effect of its treatment, provided it is measured under standardized conditions.

Prevalence of Raynaud's phenomenon in 2 ethnic groups in the general population of Estonia.

OBJECTIVE: To compare the prevalence of Raynaud's phenomenon (RP) in 2 genetically different ethnic groups in Estonia: Estonians, who are Finno-Ugric people, and Slavs, who are Indo-European people, and to investigate the risk factors of RP. METHODS: A random sample of 5248 Estonians and 4341 Slavs were surveyed by mail questionnaire (Phase I) for suspected RP. A subsample of 1739 subjects was interviewed and examined (Phase II) to make a formal diagnosis of RP, using the color charts, and to collect additional pertinent information. RESULTS: Of these 1739 subjects examined in Phase II, 226 women and 162 men were diagnosed to have RP. The age adjusted prevalence of RP was significantly higher among Slavs (women 11.4 +/- 1.3%, men 13.0 +/- 1.6%) compared to Estonians (women 7.8 +/- 1.0%, p = 0.023; men 8.2 +/- 1.5%, p = 0.031). Based on logistic regression analysis, the diagnosis of RP among women was associated with a Slavic ethnic origin, the presence of connective tissue disorders or cardiovascular diseases, a family history of RP, a history of dysphagia and frostbite, smoking, and a lower body mass index (BMI). Among men RP was associated with manual work, vibrating tool use, a history of frostbite and injuries to the fingers. older age, and a lower BMI. CONCLUSION: Our results revealed a significant difference in the prevalence of RP between 2 ethnic groups living in the same geographic region. The risk factors associated with RP show considerable sex differences, RP being mostly constitutional in women and occupational in men.

Geographic variation in the prevalence of Raynaud's phenomenon: a 5 region comparison.

OBJECTIVE: To determine the population based prevalence of Raynaud's phenomenon (RP) in 5 geographic regions: one in South Carolina, USA, and 4 in France; to explore the relationship of RP to the climate; to investigate possible risk factors; and to describe the characteristics of RP+ subjects in the general population. METHODS: The study consisted of 2 phases: a telephone survey of a randomly drawn sample of households, with 10,149 completed interviews; these were followed by a face to face interview and clinical evaluation (n = 1,534), including diagnosis of RP. The same methodology was used in all 5 regions: for recruitment of subjects, criteria for RP, method of RP diagnosis, and for gathering additional information. RESULTS: The prevalence of RP was found to be related to the climate. The relationship between RP and climate was complicated, however, by the fact that many subjects had moved between climate zones. The relationship of RP to a cold climate became more evident after taking the migration patterns into account: the majority of RP+ subjects in the 2 coldest regions had lived all their lives in the same or a similar climate zone; the majority of RP+ subjects in the 2 warmest regions had previously lived in a colder climate. Other factors associated with RP were family history of RP, cardiovascular diseases, older age, a low body mass index, use of vibrating tools, and outings of a day or more. The classical triphasic RP was rarely encountered in the general population and the most frequently observed signs and symptoms during an RP attack were blanching accompanied by numbness. CONCLUSION: In addition to being a triggering factor for RP attacks, cold also appears to be an etiologic factor in the pathogenesis of RP. A subclinical cold injury, more likely to occur in colder climates, may be responsible for the "local fault" that has been implicated in the pathogenesis of RP and, in association with other risk factors, may predispose subjects to develop clinical RP.

Prevalence of Raynaud phenomenon in Tartu and Tartumaa, southern Estonia.

The aim of the present study was to estimate the prevalence of Raynaud phenomenon (RP) among Estonians in the general population of Southern Estonia. A random sample of 2626 Estonian subjects from the general population was asked about their fingers' sensitivity to cold and color changes by a mail survey. A subsample of 457 subjects was examined to confirm the diagnosis of RP, using a standard interview assisted by color charts (a color scale and hand photographs). In addition to a short clinical examination, the nailfold capillaries were examined by in vivo microscopy and a blood sample was drawn for ANA testing. The prevalence of RP, based on the presence of blanching, alone or with cyanosis, was 8.3% +/- 0.91% (SE) for women and 7.9% +/- 1.62% for men. The prevalence increased with age and, in men, was related to occupation. Smoking was also associated with RP among men but the effect was difficult to separate from that of the occupational influences because of the high proportion (84.2%) of current and past smokers among male manual workers. RP among the Estonians in Southern Estonia has a lower prevalence than in other countries with comparable climate, its female to male ratio is low, and it is related to occupation and smoking in men.

Prevalence of scleroderma spectrum disorders in the general population of Estonia.

The purpose of this study was to estimate the prevalence of scleroderma spectrum disorders (SDS) in the general population of Estonia while taking into account environmental and ethnic factors. A random sample of 14,467 subjects from the general population were surveyed by mail questionnaire to detect those with suspected Raynaud phenomenon (RP) and SDS. A subsample of 2,154 participants was then seen during the field study to confirm the RP diagnosis and to perform a short clinical examination. Of 581 subjects with RP, 13 cases (all women) were diagnosed as having SDS; based on these findings, the estimated prevalence of SDS in the adult population is 228 per 100,000 (95% CL 121; 391), while in women alone it is 354 per 100,000 (95% CL 188; 605). The best estimate of SD (systemic scleroderma), based on ACR criteria, is 35 per 100,000 (95% CL 4; 127). No significant difference in SDS prevalence was found between the two environmentally different regions we studied. Although statistically not significant, the prevalence of SDS, especially of SD and CREST syndrome, among Russians was higher than among Estonians, as we had hypothesized. The distribution of SDS subtypes also suggests an ethnic difference. The overall prevalence of SD/CREST that we found is higher than that reported in studies not based on a random sample of the general population.

Digital vascular responses to cooling in subjects with cold sensitivity, primary Raynaud's phenomenon, or scleroderma spectrum disorders.

OBJECTIVE: To define differences in digital vascular responses to cooling and to determine their usefulness for the differential diagnosis of 4 groups of subjects: patients with primary Raynaud's phenomenon (RP) (n = 96), patients with RP associated with scleroderma (systemic sclerosis, SSc) spectrum disorders (SSc spectrum RP) (n = 108), subjects complaining of cold sensitivity of the fingers (n = 88), and RP negative controls (n = 120). METHODS: Digital systolic blood pressure, digital blood flow, and digital skin temperature were measured in a temperature controlled room at 18 or 23 degrees C; the effect of local finger cooling was tested at 30, 20, 15, and 10 degrees C. RESULTS: Digital blood pressure responses clearly differentiate the 4 diagnostic groups from each other. By contrast, blood flow and skin temperature measurements, although showing different group means, fail to reach statistical significance due to a large variance. Digital pressure responses have high sensitivity and specificity for distinguishing not only between patients with RP and controls, but also between the 2 types of RP. A relative digital systolic pressure (digital systolic pressure over brachial systolic pressure) of less than 70% at low local finger cooling temperatures (15 and 10 degrees C) has a sensitivity of 97.1% in differentiating SSc spectrum RP from primary RP. A zero reopening pressure shows a specificity of 100% at 30 degrees C and 81.7% at 20 degrees C to separate the 2 groups. The zero reopening pressure is seldom associated with clinically visible RP (10.3% among SSc spectrum RP, 4.3% among primary RP). Although the study was not designed to investigate drug effects, our data from patients who failed to abstain from vasodilators, as instructed, show they have a protective effect at 15 and 10 degrees C. CONCLUSION: The digital pressure response to cooling is a useful test for RP and cold sensitive subjects. It has high sensitivity and specificity to differentiate between SSc spectrum RP and primary RP and between primary RP and cold sensitive subjects. Our preliminary data on vasodilator use suggest that the digital pressure response to cooling may also be useful in RP treatment studies.