Genome-wide association study identifies genetic variants which predict the response of bone mineral density to teriparatide therapy.

OBJECTIVES: Teriparatide (TPTD) is an effective treatment for osteoporosis but the individual response to therapy is variable for reasons that are unclear. This study aimed to determine whether the response to TPTD might be influenced by genetic factors. METHODS: We searched for predictors of the response of bone mineral density (BMD) to TPTD using a two-stage genome-wide association study in 437 patients with osteoporosis from three referral centres. Demographic and clinical data including the response of BMD to treatment at the lumbar spine and hip were extracted from the medical records of each participant. RESULTS: Allelic variation at rs6430612 on chromosome 2, close to the CXCR4 gene was associated with the response of spine BMD to TPTD at a genome wide significant level (p=9.2×10-9 beta=-0.35 (-0.47 to -0.23)). The increase in BMD was almost twice as great in AA homozygotes at rs6430612 as compared with GG homozygotes with intermediate values in heterozygotes. The same variant was also associated with response of femoral neck and total hip BMD (p=0.007). An additional locus on chromosome 19 tagged by rs73056959 was associated with the response of femoral neck BMD to TPTD (p=3.5×10-9, beta=-1.61 (-2.14 to -1.07)). CONCLUSIONS: Genetic factors influence the response to TPTD at the lumbar spine and hip with a magnitude of effect that is clinically relevant. Further studies are required to identify the causal genetic variants and underlying mechanisms as well as to explore how genetic testing for these variants might be implemented in clinical practice.

Incorporating gout guideline advice into urate reports is associated with reduced hospital admissions: results of an observational study.

OBJECTIVE: To evaluate the impact of incorporating treatment guidance into reporting of urate test results. METHODS: Urate targets for clinically confirmed gout were added to urate results above 0.36 mmol/l requested after September 2014 within NHS Lothian. Scotland-wide data on urate-lowering therapy prescriptions and hospital admissions with gout were analysed between 2009 and 2020. Local data on urate tests were analysed between 2014 and 2015. RESULTS: Admissions with a primary diagnosis of gout in Lothian reduced modestly following the intervention from 111/year in 2010-2014 to 104/year in 2015-2019, a non-significant difference (P = 0.32). In contrast there was a significant increase in admissions to remaining NHS Scotland health boards (556/year vs 606/year, P < 0.01). For a secondary diagnosis of gout the number of admissions in NHS Lothian reduced significantly (58/year vs 39/year, P < 0.01) contrasting with a significant increase in remaining Scottish health boards (220/year vs 290/year, P < 0.01). The relative rate of admissions to NHS Lothian compared with remaining Scottish boards using a 2009 baseline were significantly reduced for both primary diagnosis of gout (1.06 vs 1.25, P < 0.001) and secondary diagnoses of gout (0.64 compared with 1.4, P < 0.001) after the intervention; however, there was no difference before the intervention. A relative increase in the prescription rates of allopurinol 300 mg tablets and febuxostat 120 mg tablets may have contributed to the improved outcomes seen. CONCLUSION: Incorporation of clinical guideline advice into routine reporting of urate results was associated with reduced rates of admission with gout in NHS Lothian, in comparison with other Scottish health boards.

Evaluation of supported self-management in gout (GoutSMART): a randomised controlled feasibility trial.

BACKGROUND: Improved outcomes for patients with gout are associated with the control of urate levels; yet, less than 40% of patients in the UK are currently offered urate lowering therapy, and it is typically offered without titration to target. Supported self-management has been shown to benefit patients with chronic health conditions; therefore, we aimed to determine whether a supported gout self-management approach, incorporating treatment-to-target urate, helped participants reach target urate levels. METHODS: In this randomised controlled feasibility study, conducted in one hospital in Edinburgh, UK, we included patients (aged ≥18 years) with gout and a physician recommendation for initiation or escalation of urate lowering therapy. We randomised participants in a 2:1 ratio to a supported self-management group or a usual care group using the GoutSMART smartphone app. Participants in the self-management group were given a urate self-testing meter and received direct advice from clinicians on escalation of urate lowering therapy through the app. Participants were identified following referral to rheumatology, or using the Scottish Health Research Register, and they were screened and offered a detailed management plan before randomisation. Participants in the usual care group had a limited version of the app, which only allowed it to function as a health diary, and their gout management plan was implemented by their general practitioner. The primary outcome was the percentage of participants achieving a urate target of 0·30 mmol/L or less at 24 weeks, and analysis was by intent to treat. The trial was registered with ClinicalTrials.gov, NCT03274063, and there is an extension study ongoing. There was no masking of participants or assessors. FINDINGS: Between April 5, 2019, and March 19, 2020, 60 (65%) of 92 patients screened were enrolled to the study. The mean age was 52.8 years (SD 14.6); 56 (93%) of the participants were male, and 4 (7%) were female. 58 (97%) of participants were White. 40 participants were assigned to the self-supported management group and 20 participants were assigned to the usual care group. A urate target of 0·30 mmol/L or less at 24 weeks was reached by 29 (73%) participants in the supported self-management group compared with 3 (15%) participants in the usual care group (risk difference 0·58 [95% CI 0·37-0·78]; p<0·0001). 90% of participants completed the study with no difference in the drop-out rate or adverse events between the two groups. INTERPRETATION: Supported self-management of gout results in substantially improved attainment of urate targets compared with usual care, and it is well tolerated. Larger trials will be needed to fully evaluate the clinical and cost-effectiveness of this approach. FUNDING: Edinburgh & Lothians Health Foundation.

Review of Current Real-World Experience with Teriparatide as Treatment of Osteoporosis in Different Patient Groups.

Teriparatide has proven effective in reducing both vertebral and non-vertebral fractures in clinical trials of post-menopausal and glucocorticoid-induced osteoporosis. Widespread adoption of Teriparatide over the last two decades means that there is now substantial experience of its use in routine clinical practice, which is summarized in this paper. Extensive real-world experience of Teriparatide in post-menopausal osteoporosis confirms the fracture and bone density benefits seen in clinical trials, with similar outcomes identified also in male and glucocorticoid-induced osteoporosis. Conversely, very limited experience has been reported in pre-menopausal osteoporosis or in the use of Teriparatide in combination with other therapies. Surveillance studies have identified no safety signals relating to the possible association of Teriparatide with osteosarcoma. We also review the evidence for predicting response to Teriparatide in order to inform the debate on where best to use Teriparatide in an increasingly crowded therapeutic landscape.

Long-Term Effects of Teriparatide Followed by Antiresorptive Therapy on Clinical Outcomes in Patients with Severe Spinal Osteoporosis.

Teriparatide (TPTD) is the most widely used anabolic agent in the treatment of patients with osteoporosis although its use is restricted in many countries. A recent randomised trial confirmed that TPTD was superior to risedronate at preventing vertebral fractures over a 2-year period. There is limited information on the relative effectiveness of TPTD compared with standard care in routine clinical practice. In this paper, we report the results of an extended observational study of 724 women referred to a specialist clinic with severe osteoporosis over an 11.5-year period, who were considered for TPTD therapy. Of these patients, 496 (68.5%) were treated with TPTD, whereas the remaining 228 (31.5%) received other treatments. This was either because they were unwilling or unable to self-inject (52.6%), because they had already been established on oral bisphosphonates (31.1%) or because of contraindications (12.7%). The TPTD group were younger than the standard care group (69.6 vs. 74.1 years) and had a lower 10-year fracture risk (25.7% vs. 28.6%). Those treated with TPTD had a greater increase in BMD at the lumbar spine compared with standard care (13.3% vs. 8.2%, p < 0.001) after approximately 2 years and had a lower incidence of vertebral fractures (4.8% vs. 10.1%, p = 0.01) over the course of our observation. There was no difference between groups with respect to either BMD change at the femoral neck or incidence of non-vertebral fractures. This study confirms that TPTD is superior to standard care at reducing the risk of vertebral fracture in patients with severe osteoporosis.

Autoantibodies to Osteoprotegerin are Associated with Low Hip Bone Mineral Density and History of Fractures in Axial Spondyloarthritis: A Cross-Sectional Observational Study.

Osteoporosis is a recognised complication of axial spondyloarthritis (axSpA) and is thought to be due to functional impairment and the osteoclast-activating effects of proinflammatory cytokines. The development of autoantibodies to OPG (OPG-Ab) has been associated with severe osteoporosis and increased bone resorption in rheumatoid arthritis. In this study, we screened for the presence of OPG-Ab in axSpA and reviewed their clinical significance. We studied 134 patients, recruited from two centres in the United Kingdom. Their mean age was 47.5 years and 75% were male. Concentrations of OPG-Ab were related to bone mineral density (BMD) and fracture history using linear and logistic regression models adjusting for age, gender, disease duration and activity, body mass index and bisphosphonate use. We detected OPG-Ab in 11/134 patients (8.2%). Femoral neck and total hip BMD were significantly reduced in OPG-Ab positive patients (0.827 vs. 0.967 g/cm2, p = 0.008 and 0.868 vs. 1.028 g/cm2, p = 0.002, respectively). Regression analysis showed that the presence of OPG-Ab was independently associated with total hip osteopenia (ORadj 24.2; 95% CI 2.57, 228) and history of fractures (ORadj 10.5; 95% CI 2.07, 53.3). OPG-Ab concentration was associated with total hip BMD in g/cm2 (ß = -1.15; 95% CI -0.25, -0.04). There were no associations between OPG-Ab concentration and bone turnover markers, but free sRANKL concentrations were lower in OPG-Ab-positive patients (median 0.04 vs. 0.11 pmol/L, p = 0.050). We conclude that OPG-Ab are associated with hip BMD and fractures in axSpA suggesting that they may contribute to the pathogenesis of bone loss in some patients with this condition.

Replication of association of the apolipoprotein A1-C3-A4 gene cluster with the risk of gout.

OBJECTIVE: Gout is associated with dyslipidaemia. Association of the apolipoprotein A1-C3-A4 gene cluster with gout has previously been reported in a small study. To investigate a possible causal role for this locus in gout, we tested the association of genetic variants from APOA1 (rs670) and APOC3 (rs5128) with gout. METHODS: We studied data for 2452 controls and 2690 clinically ascertained gout cases of European and New Zealand Polynesian (Maori and Pacific) ancestry. Data were also used from the publicly available Atherosclerosis Risk in Communities study (n = 5367) and the Framingham Heart Study (n = 2984). Multivariate adjusted logistic and linear regression was used to test the association of single-nucleotide polymorphisms with gout risk, serum urate, triglyceride and high-density lipoprotein cholesterol (HDL-C). RESULTS: In Polynesians, the T-allele of rs670 (APOA1) increased (odds ratio, OR = 1.53, P = 4.9 × 10(-6)) and the G-allele of rs5128 (APOC3) decreased the risk of gout (OR = 0.86, P = 0.026). In Europeans, there was a strong trend to a risk effect of the T-allele for rs670 (OR = 1.11, P = 0.055), with a significant protective effect of the G-allele for rs5128 being observed after adjustment for triglycerides and HDL-C (OR = 0.81, P = 0.039). The effect at rs5128 was specific to males in both Europeans and Polynesians. Association in Polynesians was independent of any effect of rs670 and rs5128 on triglyceride and HDL-C levels. There was no evidence for association of either single-nucleotide polymorphism with serum urate levels (P ⩾ 0.10). CONCLUSION: Our data, replicating a previous study, supports the hypothesis that the apolipoprotein A1-C3-A4 gene cluster plays a causal role in gout.

Patient rated outcomes study into the surgical interventions available for the rheumatoid hand and wrist.

INTRODUCTION: A multitude of surgical interventions are recognised for the treatment of the rheumatoid hand and wrist, however there seems to be a distinct lack of patient rated outcome measures (PROMs) studies reporting on the efficacy of these procedures. The aim of this study was to assess the PROMs related to hand and wrist surgery in patients with rheumatoid arthritis (RA). MATERIALS AND METHODS: A single surgeon series identified 94 patients (133 hands) with RA who had undergone one of eight surgical procedures (Swanson's arthroplasty, finger joint or wrist arthrodesis, carpal tunnel decompression, posterior interosseous nerve denervation, RA nodule excision, synovectomy/tenosynovectomy and tendon repair/release) with a mean follow-up period of 3 years. The primary outcome measures were the same for all patients and comprised the validated modified score for the assessment and quantification of chronic rheumatoid affections of the hand (M-SACRAH) and a separate satisfaction questionnaire. RESULTS: Highly significant improvements in both function and pain scores are reported across the cohort as a whole following hand surgery, with this pattern replicated within all of the operative subgroups. In keeping with these favourable results very high levels of overall satisfaction were reported with 93 % of patients reporting themselves to be very or fairly satisfied with their procedure. CONCLUSIONS: Overall, patient reported outcomes in functional, stiffness and pain domains of the M-SACRAH questionnaire appear very favourable across the range of surgical procedures that can be performed in the rheumatoid hand. We believe this data supports the use of all the procedures explored, and will be helpful in patient guidance.

The Toll-Like Receptor 4 (TLR4) Variant rs2149356 and Risk of Gout in European and Polynesian Sample Sets.

Deposition of crystallized monosodium urate (MSU) in joints as a result of hyperuricemia is a central risk factor for gout. However other factors must exist that control the progression from hyperuricaemia to gout. A previous genetic association study has implicated the toll-like receptor 4 (TLR4) which activates the NLRP3 inflammasome via the nuclear factor-κB signaling pathway upon stimulation by MSU crystals. The T-allele of single nucleotide polymorphism rs2149356 in TLR4 is a risk factor associated with gout in a Chinese study. Our aim was to replicate this observation in participants of European and New Zealand Polynesian (Maori and Pacific) ancestry. A total of 2250 clinically-ascertained prevalent gout cases and 13925 controls were used. Non-clinically-ascertained incident gout cases and controls from the Health Professional Follow-up (HPFS) and Nurses Health Studies (NHS) were also used. Genotypes were derived from genome-wide genotype data or directly obtained using Taqman. Logistic regression analysis was done including age, sex, diuretic exposure and ancestry as covariates as appropriate. The T-allele increased the risk of gout in the clinically-ascertained European samples (OR = 1.12, P = 0.012) and decreased the risk of gout in Polynesians (OR = 0.80, P = 0.011). There was no evidence for association in the HPFS or NHS sample sets. In conclusion TLR4 SNP rs2143956 associates with gout risk in prevalent clinically-ascertained gout in Europeans, in a direction consistent with previously published results in Han Chinese. However, with an opposite direction of association in Polynesians and no evidence for association in a non-clinically-ascertained incident gout cohort this variant should be analysed in other international gout genetic data sets to determine if there is genuine evidence for association.

Multiplicative interaction of functional inflammasome genetic variants in determining the risk of gout.

INTRODUCTION: The acute gout flare results from a localised self-limiting innate immune response to monosodium urate (MSU) crystals deposited in joints in hyperuricaemic individuals. Activation of the caspase recruitment domain-containing protein 8 (CARD8) NOD-like receptor pyrin-containing 3 (NLRP3) inflammasome by MSU crystals and production of mature interleukin-1ß (IL-1ß) is central to acute gouty arthritis. However very little is known about genetic control of the innate immune response involved in acute gouty arthritis. Therefore our aim was to test functional single nucleotide polymorphism (SNP) variants in the toll-like receptor (TLR)-inflammasome-IL-1ß axis for association with gout. METHODS: 1,494 gout cases of European and 863 gout cases of New Zealand (NZ) Polynesian (Maori and Pacific Island) ancestry were included. Gout was diagnosed by the 1977 ARA gout classification criteria. There were 1,030 Polynesian controls and 10,942 European controls including from the publicly-available Atherosclerosis Risk in Communities (ARIC) and Framingham Heart (FHS) studies. The ten SNPs were either genotyped by Sequenom MassArray or by Affymetrix SNP array or imputed in the ARIC and FHS datasets. Allelic association was done by logistic regression adjusting by age and sex with European and Polynesian data combined by meta-analysis. Sample sets were pooled for multiplicative interaction analysis, which was also adjusted by sample set. RESULTS: Eleven SNPs were tested in the TLR2, CD14, IL1B, CARD8, NLRP3, MYD88, P2RX7, DAPK1 and TNXIP genes. Nominally significant (P < 0.05) associations with gout were detected at CARD8 rs2043211 (OR = 1.12, P = 0.007), IL1B rs1143623 (OR = 1.10, P = 0.020) and CD14 rs2569190 (OR = 1.08; P = 0.036). There was significant multiplicative interaction between CARD8 and IL1B (P = 0.005), with the IL1B risk genotype amplifying the risk effect of CARD8. CONCLUSION: There is evidence for association of gout with functional variants in CARD8, IL1B and CD14. The gout-associated allele of IL1B increases expression of IL-1ß - the multiplicative interaction with CARD8 would be consistent with a synergy of greater inflammasome activity (resulting from reduced CARD8) combined with higher levels of pre-IL-1ß expression leading to increased production of mature IL-1ß in gout.

Characterisation of osteoprotegerin autoantibodies in coeliac disease.

Autoantibodies neutralising the effect of the bone regulatory cytokine osteoprotegerin (OPG) have been described in a patient with severe osteoporosis and coeliac disease. This study aimed to determine the prevalence and epitope specificity of autoantibodies to OPG in patients with coeliac disease, and correlate their presence with bone mineral density. A direct enzyme-linked immunosorbent assay was developed and used to screen patients with coeliac disease for autoantibodies to OPG. Recombinant fragments of OPG were made to evaluate the epitope specificity and affinity of these antibodies. Phenotype information of the patients was obtained by case note review. Raised titres of antibodies to OPG were found in 7/71 (9.8 %) patients with coeliac disease, compared with 1/72 (1.4 %) non-coeliac osteoporosis clinic control patients (p < 0.05). Our results suggest that a polyclonal antibody response to OPG is raised in these patients capable of recognising different epitopes of OPG with varying affinity. The titre of OPG antibodies was associated with lower bone mineral density Z-score of the hip in coeliac patients on univariate (p < 0.05) and multivariate analysis including age, sex height and weight as covariates (p < 0.01). Polyclonal antibodies to OPG are more common in patients with coeliac disease and are independently associated with lower bone mineral density Z-scores of the hip. Further work is required to establish the clinical utility of testing for OPG antibodies.

Functional and patient-reported outcome of partial wrist denervation versus the Mannerfelt wrist arthrodesis in the rheumatoid wrist.

INTRODUCTION: Wrist arthrodesis offers high success rates in patients with rheumatoid arthritis; however, loss of residual mobility may cause unnecessary disability. This makes wrist denervation an appealing alternative. However, there is a distinct lack of patient-reported outcome measure studies comparing these two procedures. The aim of this study was to report any change in function, pain and satisfaction following wrist arthrodesis compared to denervation in a single surgeon series of rheumatoid patients. PATIENTS AND METHODS: The results of 16 wrist arthrodesis in 15 patients and 14 partial (PIN) wrist denervations in 13 patients were compared with a mean follow-up period of 39 and 22 months, respectively. The primary outcome measures were the same for both groups and included the validated patient-rated wrist evaluation questionnaire and a satisfaction questionnaire. RESULTS: Wrist arthrodesis significantly improved the mean total pain and functional outcome scores by 54 and 36 %, respectively, at the time of follow-up. Wrist denervation patients also reported significant improvements of 44 and 42 % in total pain and functional outcomes, respectively; 87 % reported being very satisfied with their wrist arthrodesis procedure compared to 78 % in the denervation group. No statistically significant difference in response between the groups was observed in this series of patients. CONCLUSIONS: Both procedures enjoyed favourable results amongst patients with excellent satisfaction outcomes. PIN denervation is a simple procedure with low complication rates and we therefore consider it a valid alternative to more difficult treatment options, such as partial or total wrist arthrodesis.

Prevalence and clinical prediction of osteoporosis in a contemporary cohort of patients with rheumatoid arthritis.

OBJECTIVE: Osteoporosis has previously been reported to be twice as common in patients with RA as in controls, but these studies predate the introduction of aggressive management of RA. The aim of this study was to evaluate the prevalence and clinical predictors of osteoporosis in RA in a contemporary cohort and to develop a clinical tool for the identification of patients at risk. METHODS: The prevalence of osteoporosis was related to clinical and demographic variables in 304 consecutive RA patients undergoing DXA at a single centre between 2009 and 2010 and compared with the frequency of osteoporosis in a population-based cohort of 903 subjects. RESULTS: The RA cohort was predominantly female (81.9%), with an average age of 63.5 years (s.d. 11.8) and a disease duration of 9.6 years (s.d. 10.2). Osteoporosis was present in 91 (29.9%) patients at either the spine or total hip compared with 157/903 (17.4%) of age- and gender-matched controls. In RA patients, osteoporosis was associated with female gender (P = 0.002), age (P < 0.001), time since menopause (P < 0.001), BMI (P < 0.001), ESR (P = 0.006), Larsen score (P = 0.011) and co-morbidities (P = 0.020), but logistic regression analysis showed that only age and BMI were independent predictors. A predictive tool based on age and BMI was developed that had 91.4% sensitivity for the detection of osteoporosis in an independent RA population. CONCLUSION: The prevalence of osteoporosis in RA remains high in the modern era despite aggressive management and the use of biologic therapy. Most RA patients with osteoporosis can be identified by a simple algorithm taking age and BMI into account.

Up-titration of allopurinol in patients with gout.

OBJECTIVES: European League against Rheumatism (EULAR) gout management guidelines recommend achieving a target urate level <6.0 mg/dL (<357 µmol/L). Allopurinol is the most widely used urate-lowering therapy; however, many gout patients who are prescribed allopurinol do not have urate levels optimally controlled. The objective of this analysis was to review the efficacy and tolerability of allopurinol up-titration in achieving the EULAR target levels. METHOD: The Febuxostat versus Allopurinol Streamlined Trial (FAST) is an ongoing multi-centre study comparing the cardiovascular safety of febuxostat and allopurinol (target recruitment: 5706 patients). Recruited patients were already taking allopurinol and the protocol required up-titration of daily allopurinol dose, in 100 mg increments, to achieve the EULAR urate target level prior to randomisation. We reviewed pre-randomisation data from the first 400 recruited and subsequently randomised FAST patients. RESULTS: Of 400 patients, 144 (36%) had urate levels ≥357 µmol/L at screening and required allopurinol up-titration. Higher urate levels were significantly associated with lower allopurinol dose, male sex, increased BMI, increased alcohol intake and diuretic use. Mean fall in urate levels after a single 100-mg dose increase was 71 µmol/L. The number of up-titrations required ranged from one to five (median = 1) with 65% of patients controlled after one 100-mg up-titration. Overall, 97% of up-titrated patients achieved target urate levels with median final allopurinol dose of 300 mg daily. Side effects and complications of up-titration were minimal. CONCLUSION: Overall, 36% of FAST patients were not at target urate levels and required up-titration. Allopurinol up-titration was effective in achieving urate target levels and was generally well tolerated by patients.

Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone.

RANK (receptor activator of nuclear factor-κB), encoded by TNFRSF11A, is a key protein in osteoclastogenesis. TNFRSF11A mutations cause Paget's disease of bone (PDB)-like diseases (ie, familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset PDB) and an osteoclast-poor form of osteopetrosis. However, no TNFRSF11A mutations have been found in classic PDB, neither in familial nor in isolated cases. To investigate the possible relationship between TNFRSF11A polymorphisms and sporadic PDB, we conducted an association study including 32 single-nucleotide polymorphisms (SNPs) in 196 Belgian sporadic PDB patients and 212 control individuals. Thirteen SNPs and 3 multimarker tests (MMTs) turned out to have a p value of between .036 and 3.17 × 10(-4) , with the major effect coming from females. Moreover, 6 SNPs and 1 MMT withstood the Bonferroni correction (p < .002). Replication studies were performed for 2 nonsynonymous SNPs (rs35211496 and rs1805034) in a Dutch and a British cohort. Interestingly, both SNPs resulted in p values ranging from .013 to 8.38 × 10(-5) in both populations. Meta-analysis over three populations resulted in p = .002 for rs35211496 and p = 1.27 × 10(-8) for rs1805034, again mainly coming from the female subgroups. In an attempt to identify the underlying causative SNP, we performed functional studies for the coding SNPs as well as resequencing efforts of a 31-kb region harboring a risk haplotype within the Belgian females. However, neither approach resulted in significant evidence for the causality of any of the tested genetic variants. Therefore, further studies are needed to identify the real cause of the increased risk to develop PDB shown to be present within TNFRSF11A.

Osteoporosis associated with neutralizing autoantibodies against osteoprotegerin.

Autoantibodies against osteoprotegerin, which block the inhibitory effect of osteoprotegerin on signaling by the receptor activator of nuclear factor (NF)-kappaB (RANK), were identified in a man with celiac disease who presented with severe osteoporosis and high bone turnover. The osteoporosis did not respond to the treatment of his celiac disease but was completely reversed by bisphosphonate therapy. Autoantibodies against osteoprotegerin were detected in three additional patients with celiac disease. Such autoantibodies may be associated with the development of high-turnover osteoporosis, but whether autoantibodies against osteoprotegerin commonly contribute to the pathogenesis of osteoporosis in patients with celiac disease remains to be determined.

Recent insights into the pathogenesis of hyperuricaemia and gout.

Gout is a common rheumatic disease in humans which is characterized by elevation in serum uric acid levels, and deposition of uric acid crystals in the joint. Hyperuricaemia is the primary risk factor for the development of gout and primates have uniquely high levels of serum uric acid due to missense mutations in the uricase gene. Levels of serum uric acid are known to be highly heritable, and mutations in genes which encode enzymes in the purine salvage pathway have long been recognized as rare causes of gout. Until recently, however, little has been known about the genetic determinants of urate metabolism and susceptibility to gout in the general population. Over recent months, a series of large scale genome wide association studies have been performed which have shed new light on the genes which regulate serum uric acid levels and susceptibility to gout. Most of these genes seem to be involved in regulating the renal excretion of uric acid which underscores the importance of reduced urate excretion as opposed to increased endogenous production as a cause of gout. Further work will now be required to investigate the mechanisms by which these genetic variants regulate urate excretion and serum urate levels. However, it seems likely that the genes so far identified will represent new molecular targets for the design of drugs to enhance urate excretion and the genetic variants that predispose to gout might be of value as genetic markers of susceptibility to gout.

Clinical and biochemical response of TNFRSF11A-mediated early-onset familial Paget disease to bisphosphonate therapy.

Early-onset familial Paget disease of bone (EoPDB) is a rare condition caused by a 27-bp insertion mutation affecting the signal peptide of TNFRSF11A, which encodes RANK. EoPDB shows phenotypic overlap to both familial expansile osteolysis and expansile skeletal hyperphosphatasia, which are caused by similar mutations in TNFRSF11A. Although EoPDB is characterized by elevated bone turnover, there is no published information on the response of this condition to antiresorptive therapy. Here, we describe the clinical and biochemical response to bisphosphonate therapy in three patients with EoPDB. In all cases, treatment with the first-generation bisphosphonate etidronate at high doses reduced biochemical markers of bone turnover but the response was incomplete and short-lived. In contrast, treatment with aminobisphosphonates resulted in greater suppression of biochemical markers of bone turnover with an extended duration of response. From a clinical perspective, the results were less impressive and there was no clear benefit from antiresorptive treatment in terms of bone deformity, deafness, and tooth loss, although bone pain improved in one patient. We conclude that intravenous aminobisphosphonate therapy may be the preferred mode of treatment for EoPDB to provide long-term suppression of bone turnover. The long-term clinical effects of treatment on the natural history of the bone disease remain uncertain however, and this will require further study.