Increased workload without clinical benefit: Results following implementation of the ACR-TIRADS system for thyroid nodules.

OBJECTIVE: The ACR-TIRADS system for stratifying thyroid nodule malignancy risk has been widely promoted and implemented. We audited its introduction at a large public hospital in Auckland, New Zealand. DESIGN: Audit of outcomes following thyroid nodule fine needle aspiration (FNA) before/after ACR-TIRADS. PATIENTS: Individuals undergoing thyroid FNA 2017-2019. MEASUREMENTS: From medical records, we obtained details from the pre-FNA ultrasound (nodule size, TIRADS points/levels, radiologist recommendation for FNA), Bethesda (B) cytology classification, histology and post-FNA follow-up. RESULTS: Four hundred and twenty-two individuals had 564 FNAs, 163 had surgery and 54 (13%) had cancer in the primary nodule. 37/54 (69%) cancers were papillary thyroid carcinoma (median size 25 mm, 87% ≥10 mm, 61% ≥20 mm). Following ACR-TIRADS introduction, FNA recommendations increased greater than twofold, FNAs performed by 71%-83%, and the monthly rate of FNAs and operations by 60% and 40%, respectively. However, the proportion of cancers/FNA remained similar (9.9% post-TIRADS vs. 8.7% pre-TIRADS). The proportions of FNA results remained stable for B2-B4 categories, but doubled (11% vs. 5%) for B5-B6: 15 FNAs were needed to identify an additional B5/B6 lesion. TIRADS-5 nodules had a higher proportion of B5/B6 (20%) and a lower proportion of B2 (30%) than TIRADS-3 (2%, 57%, respectively) and TIRADS-4 (9%, 56%) nodules. About 5 additional cancers/year were diagnosed, but they were more often small (49% vs. 8% <2 cm, 17% vs. 0% <1 cm). CONCLUSION: ACR-TIRADS introduction increased workload (FNAs and operations), without increasing the proportion of cancers/FNA. It led to a few more cancers being diagnosed, but many were small and of uncertain clinical significance.

Diversity of invited speakers at endocrinology conferences.

OBJECTIVE: To assess diversity of gender and geographical location of institutional affiliation among invited speakers at major international endocrinology conferences. DESIGN AND METHODS: Descriptive study of characteristics of invited speakers at eight general and discipline-specific endocrinology conferences held annually in Europe and North America 2013-2019. Main outcomes were gender, geographical location of institutional affiliation and frequency of repeat presentations among invited speakers. RESULTS: Of 2375 invited speakers who gave 3522 presentations, 843 (35.5%) were women. Five hundred and ninety-four (25.0%) speakers gave >1 presentation at any conference. The proportion of women speakers declined as the number of presentations per speaker increased. Of speakers giving two and seven presentations, respectively, 36.0% and 20.0% were women. 52.9% of speakers were from institutions in North America, and 25.6% from institutions in Western Europe. Fewer than 5% of speakers were from institutions in each of Eastern Europe, Asia, South America, Africa and Oceania. The proportions of speakers who were women and from each geographical area were unchanged over 7 years. Up to one in three speakers gave >1 presentation at an individual conference (range 9.9%-32.2%). CONCLUSIONS: Women and speakers from institutions outside of North America and Western Europe are underrepresented among invited speakers at major international endocrinology conferences. Longitudinal data indicate no change in either speaker characteristic over the time period examined. These underrepresentations are more marked among speakers who give repeat presentations.

Fracture Prevention with Zoledronate in Older Women with Osteopenia.

BACKGROUND: Bisphosphonates prevent fractures in patients with osteoporosis, but their efficacy in women with osteopenia is unknown. Most fractures in postmenopausal women occur in those with osteopenia, so therapies that are effective in women with osteopenia are needed. METHODS: We conducted a 6-year, double-blind trial involving 2000 women with osteopenia (defined by a T score of -1.0 to -2.5 at either the total hip or the femoral neck on either side) who were 65 years of age or older. Participants were randomly assigned to receive four infusions of either zoledronate at a dose of 5 mg (zoledronate group) or normal saline (placebo group) at 18-month intervals. A dietary calcium intake of 1 g per day was advised, but calcium supplements were not provided. Participants who were not already taking vitamin D supplements received cholecalciferol before the trial began (a single dose of 2.5 mg) and during the trial (1.25 mg per month). The primary end point was the time to first occurrence of a nonvertebral or vertebral fragility fracture. RESULTS: At baseline, the mean (±SD) age was 71±5 years, the T score at the femoral neck was -1.6±0.5, and the median 10-year risk of hip fracture was 2.3%. A fragility fracture occurred in 190 women in the placebo group and in 122 women in the zoledronate group (hazard ratio with zoledronate, 0.63; 95% confidence interval, 0.50 to 0.79; P<0.001). The number of women that would need to be treated to prevent the occurrence of a fracture in 1 woman was 15. As compared with the placebo group, women who received zoledronate had a lower risk of nonvertebral fragility fractures (hazard ratio, 0.66; P=0.001), symptomatic fractures (hazard ratio, 0.73; P=0.003), vertebral fractures (odds ratio, 0.45; P=0.002), and height loss (P<0.001). CONCLUSIONS: The risk of nonvertebral or vertebral fragility fractures was significantly lower in women with osteopenia who received zoledronate than in women who received placebo. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12609000593235 .).

Prevalence of biochemical osteomalacia in adults undergoing vitamin D testing.

OBJECTIVE: Prolonged severe vitamin D deficiency can cause osteomalacia, but the 25-hydroxyvitamin D (25OHD) concentration below which this occurs is unknown. We investigated the prevalence of biochemical osteomalacia in adults with a measurement of 25OHD. DESIGN, MEASUREMENT, AND PATIENTS: 25OHD results between 1/1/2009 and 15/6/2020 were obtained from the regional laboratory database, together with measurements of serum calcium, parathyroid hormone (PTH) and alkaline phosphatase (ALP) within 6 months of the index 25OHD. We defined biochemical osteomalacia as all 3 of: albumin-adjusted serum calcium (aCa)<2.0 mmol/L, PTH>7.3 pmol/L and ALP>150 IU/L. Possible osteomalacia was 2/3 criteria with the other test not done. 25OHD measurements associated with significant renal impairment, elevated hepatic transaminases or hypercalcaemia were excluded. RESULTS: 110,046 25OHD measurements were identified over the 11.5 years period. After removal of ineligible measurements, 42,171 25OHD measurements from 32,386 individuals with at least 2 of aCa, PTH and ALP were included in analyses. Median 25OHD was 63 nmol/L; 8% were <25 nmol/L, and 33% were <50 nmol/L. Five index 25OHD measurements met the definition of biochemical osteomalacia, and another 11 were possible osteomalacia. After reviewing available clinical records for these 16 episodes, we classified 9 cases as osteomalacia and 7 as other diagnoses. Thus, the prevalence of biochemical osteomalacia was 0.02% (9/42,171) for 25OHD measurements and 0.23% (8/3432) for 25OHD<25 nmol/L. All cases of osteomalacia with 25OHD measurements prior to supplementation had 25OHD≤18 nmol/L. CONCLUSION: The prevalence of biochemical osteomalacia is very low, even in individuals with 25OHD<25 nmol/L.

Long-Term Stable Bone Mineral Density in HIV-Infected Men Without Risk Factors for Osteoporosis Treated with Antiretroviral Therapy.

INTRODUCTION: Most prospective studies of bone mineral density (BMD) in HIV-infected cohorts taking antiretroviral therapy (ART) have been of short duration, typically < 3 years. Such studies have reported short-term stable or increasing BMD. We assessed whether this BMD stability persists for > 10 years in middle-aged and older men established on ART. METHODS: A 12-year, prospective, longitudinal study in 44 HIV-infected men treated with ART who had measurements of BMD at the lumbar spine, proximal femur and total body at baseline, 2, 6 and 12 years. RESULTS: At baseline, the mean age of participants was 49 years, the mean duration of HIV infection was 8 years, and the mean duration of ART was 50 months. After 12 years, BMD increased by 6.9% (95% CI 3.4 to 10.3) at the lumbar spine, and remained stable (range of BMD change: - 0.6% to 0.0%) at the total hip, femoral neck and total body. Only two individuals had a decrease of > 10% in BMD at any site during follow-up and both decreases in BMD were explained by co-morbid illnesses. CONCLUSIONS: BMD remained stable over 12 years in middle-aged and older HIV-infected men treated with ART. Monitoring BMD in men established on ART who do not have risk factors for BMD loss is not necessary.

Controversies in medicine: the role of calcium and vitamin D supplements in adults.

Vitamin D is made in the skin when exposed to sunlight, so deficiency is usually the result of low sunlight exposure (eg, in frail older people and in individuals who are veiled). Calcium and/or vitamin D supplements have been used for the prevention and treatment of osteoporosis. The major trials in community-dwelling individuals have not demonstrated fracture prevention with either calcium, vitamin D, or their combination, but the results of a large study in vitamin D-deficient nursing home residents indicated a reduced fracture incidence. Trials show that vitamin D increases bone density when winter 25-hydroxyvitamin D levels are below 25-30 nmol/L. However, assay expense and variability suggest that supplements are better targeted based on clinical status to frail older people and possibly to people with dark skin living at higher latitudes. A daily dose of 400-800 units (10-20 µg) is usually adequate. Parenteral antiresorptive drugs can cause hypocalcaemia in severe vitamin D deficiency (< 25 nmol/L), which should therefore be corrected before treatment. Clinical trials have not demonstrated benefits of vitamin D on non-skeletal endpoints. Calcium supplements in healthy individuals are not needed, nor are they required in most people receiving treatment for osteoporosis, where they have not been shown to affect treatment efficacy. Calcium supplements cause constipation, bloating and kidney stones, and some evidence suggests they may cause a small increase in the risk of myocardial infarction. Low dose vitamin D is safe, but high doses result in more falls and fractures. Current evidence does not support the use of these supplements in healthy community-dwelling adults.

Assessment of research waste part 1: an exemplar from examining study design, surrogate and clinical endpoints in studies of calcium intake and vitamin D supplementation.

BACKGROUND: Research waste is estimated to be very common, but assessments of its prevalence and scope are rare. As an example, we assessed research waste in clinical research on calcium intake (assessing study design and endpoint type) and vitamin D supplementation (assessing endpoint type). METHODS: We examined 404 randomised controlled trials (RCTs) and observational studies of calcium intake (diet or supplements) and bone mineral density (BMD) or fracture, and 547 RCTs of vitamin D supplements, and assessed the proportion of studies that used surrogate or clinical endpoints. For studies with BMD or fracture as an endpoint, we estimated when the 'tipping' point occurred indicating the need for RCTs with fracture as an endpoint (based on cumulative meta-analyses of BMD RCTs, and chronological review of observational studies), and whether each study published at least 5y after the tipping point was novel, added new clinical knowledge or was research waste. RESULTS: Observational studies of calcium intake and BMD or fracture outnumbered RCTs by 3.3-4.5 times. For both calcium intake and vitamin D supplements, studies using surrogate endpoints outnumbered studies using clinical endpoints by 1.6-3 times. Of 41 RCT publications of calcium intake and BMD or fracture published at least 5y after the tipping point in 1994, we considered that 19 (46%) lacked novelty, another 13 (32%) added no new clinical knowledge, and 30 (73%) were research waste. Of 204 observational study publications of calcium intake and BMD or fracture, 197 (96%) lacked novelty, another 5 (2%) added no new clinical knowledge, and 202 (99%) were research waste. Of 39 RCTs of vitamin D supplementation and BMD or fracture published at least 5y after the tipping point in 1999, 14 (36%) lacked novelty, another 13 (33%) added no new clinical knowledge, and 27 (69%) were research waste. CONCLUSIONS: A high proportion of studies of calcium intake since 2000 (95%) and trials of vitamin D supplements since 2005 (69%) on BMD or fracture represent research waste.

Assessment of research waste part 2: wrong study populations- an exemplar of baseline vitamin D status of participants in trials of vitamin D supplementation.

BACKGROUND: Research waste can occur when trials are conducted in the wrong populations. Vitamin D deficient populations are most likely to benefit from vitamin D supplementation. We investigated waste attributable to randomised controlled trials (RCTs) of supplementation in populations that were not vitamin D deficient. METHODS: In December 2015, we searched Pubmed, recent systematic reviews, and three trial registries for RCTs of vitamin D with clinical endpoints in adults, and 25-hydroxvitamin D (25OHD) survey data relevant to large (N ≥ 1000) RCTs. We investigated the proportion of RCTs that studied vitamin D deficient populations, temporal trends in baseline 25OHD, and whether investigators in large RCTs considered relevant 25OHD survey data or systematic reviews in their trial justifications. RESULTS: Of 137 RCTs of vitamin D with clinical endpoints, 118 (86%) reported baseline mean/median 25OHD, which was < 25, 25-49, 50-74, and ≥ 75 nmol/L in 12 (10%), 62 (53%), 36 (31%), and 8 (7%) RCTs, respectively. In 70% of RCTs, baseline 25OHD was > 40 nmol/L. Baseline 25OHD increased over time. Before 2006, 38%, 62%, 0% and 0% of RCTs had baseline 25OHD < 25, 25-49, 50-74, and ≥ 75 nmol/L respectively; in 2011-15, the respective proportions were 9%, 49%, 37%, and 6%. Of 12 RCTs with baseline 25OHD < 25 nmol/L, 8 had neutral findings. Of 25 large RCTs (18 completed, 7 ongoing), 1 was undertaken in a vitamin D deficient population, 3 in vitamin D insufficient populations, and 17 had, or probably will have, baseline 25OHD > 40 nmol/L. 44% (8/18) of large completed RCTs cited relevant prior population 25OHD data, and only 3/10 (30%) relevant prior systematic reviews. CONCLUSIONS: Up to 70% of RCTs of vitamin D with clinical endpoints, 71% of large completed RCTs, and 100% of ongoing large RCTs could be considered research waste because they studied cohorts that were not vitamin D deficient.

Conflicts of interest and expertise of independent commenters in news stories about medical research.

BACKGROUND: Media coverage of medical research influences the views and behaviours of clinicians, scientists and members of the public. We examined how frequently commenters in news stories about medical research have relevant expertise and have academic and financial conflicts, how often such conflicts are reported and whether there are associations between the conflicts and the disposition of the comments toward the findings of the source research. METHODS: We analyzed 104 independent comments in news stories on original clinical research published in high-impact medical journals from Jan. 1 to Mar. 31, 2013, and 21 related journal editorials. Main outcomes were prevalence of relevant academic and clinical expertise, prevalence and reporting of academic and financial conflicts of interest, and disposition of comments toward study findings. RESULTS: Only 1 in 6 news stories included independent comments. Overall, 25% of commenters and 0% of editorialists had neither relevant academic nor clinical expertise (p = 0.007). Among the 104 comments, an academic conflict of interest was present for 56 (54%), of which 25 (45%) were reported in the news stories. A financial conflict of interest was present for 33 (32%) of the comments, of which 11 (33%) were reported. When commenters' conflicts of interest were congruent with the findings of the source research, 97% and 93% of comments associated with academic and financial conflicts of interest, respectively, were favourably disposed toward the research. These values were 16% and 17%, respectively, when the conflicts of interest were not congruent with the research findings. INTERPRETATION: Independent commenters in new stories about medical research may lack relevant academic or clinical expertise. Academic or financial conflicts of interest were frequently present among independent commenters but infrequently reported, and were often associated with the disposition of comments about the source research.

Duration of antiresorptive activity of zoledronate in postmenopausal women with osteopenia: a randomized, controlled multidose trial.

BACKGROUND: Intravenous zoledronate 5 mg annually reduces fracture risk, and 5 mg every 2 years prevents bone loss, but the optimal dosing regimens for these indications are uncertain. METHODS: We conducted a 3-year open-label extension of a 2-year randomized, placebo-controlled, double-blind study. Late postmenopausal women with osteopenia were assigned to receive a single baseline dose of 1 mg, 2.5 mg or 5 mg of zoledronate or placebo. The primary outcome was change in spine bone mineral density (BMD). Secondary outcomes were changes in hip BMD and serum markers of bone turnover. RESULTS: The study involved 160 women. Zoledronate increased BMD and reduced markers of bone turnover in a dose-dependent manner. After 2 years, the 1-mg, 2.5-mg and 5-mg zoledronate doses increased spine BMD over placebo by 5.0% (95% confidence interval [CI] 3.0% to 7.0%), 5.7% (95% CI 3.7% to 7.7%) and 5.7% (95% CI 3.7% to 7.6%), respectively; after 5 years, the respective increases were 2.0% (95% CI -1.1% to 5.0%), 2.2% (95% CI -1.0% to 5.4%) and 5.1% (95% CI 2.2% to 8.1%). After 2 years, the 1-mg, 2.5-mg and 5-mg zoledronate doses increased total hip BMD over placebo by 2.6% (95% CI 1.3% to 3.9%), 4.1% (95% CI 2.9% to 5.4%) and 4.7% (95% CI 3.4% to 5.9%), respectively; after 5 years, the respective increases were 1.8% (95% CI -0.1% to 3.8%), 2.8% (95% CI 0.8% to 4.8%) and 5.4% (95% CI 3.5% to 7.3%). BMD remained above baseline values for 2-3 years in the 1-mg group, 3-4 years in the 2.5-mg group and at least 5 years in the 5-mg group. INTERPRETATION: The antiresorptive activity of single zoledronate doses of 1-5 mg persist for at least 3 years in postmenopausal women with osteopenia. Clinical trials would be justified to evaluate the effects on fracture risk of less frequent or lower doses of zoledronate than are currently recommended. TRIAL REGISTRATION: www.anzctr.org.au, no. ACTRN12607000576426.

Meta-analysis of randomised trials comparing a penicillin or cephalosporin with a macrolide or lincosamide in the treatment of cellulitis or erysipelas.

PURPOSE: Beta-lactam antibiotics, such as penicillin, flucloxacillin or cephalexin, are widely considered first-line treatment for cellulitis and erysipelas, while macrolides and lincosamides, such as erythromycin, azithromycin or clindamycin, are widely considered second-line agents. We attempted to determine whether outcomes differed between patients treated either with a beta-lactam or with a macrolide or lincosamide. METHODS: We conducted a meta-analysis of published trials in which patients with cellulitis or erysipelas were randomised to treatment either with a beta-lactam or with a macrolide or lincosamide. We searched PUBMED, EMBASE, MEDLINE and SCOPUS (up to March 2014) using the terms: cellulitis/erysipelas, penicillin/beta-lactam, macrolide/lincosamide, random*/controlled*/trial* as keywords. We included randomised trials that compared monotherapy with a beta-lactam with monotherapy with a macrolide or lincosamide for cellulitis or erysipelas. RESULTS: We identified 15 studies, 9 in patients with cellulitis or erysipelas and 6 in patients with various skin and soft tissue infections including cellulitis and erysipelas. The efficacy of treatment of cellulitis or erysipelas was similar with a beta-lactam [27/221 (12 %) not cured] and a macrolide or lincosamide [21/241 (9 %) not cured, RR 1.24, 95 % CI 0.72-2.41, p = 0.44]. Treatment efficacy was also similar for skin or soft tissue infections including cellulitis and erysipelas (RR 1.28, 95 % CI 0.96-1.69, p = 0.09). Risk of adverse effects was similar for beta-lactams [148/1295 (11 %) not cured] and macrolides or lincosamides [228/1737 (13 %) not cured, RR 0.86, 95 % CI 0.64-1.16, p = 0.31]. CONCLUSION: Treatment with a macrolide or lincosamide for cellulitis or erysipelas has a similar efficacy and incidence of adverse effects as treatment with a beta-lactam.

The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis.

AIMS/HYPOTHESIS: Thiazolidinediones (TZDs) are associated with an increased risk of fracture but the mechanism is unclear. We sought to determine the effect of TZDs on bone mineral density (BMD) and bone turnover markers. METHODS: PubMed, EMBASE and Cochrane CENTRAL databases were searched from inception until January 2015 for randomised controlled trials comparing TZDs with metformin, sulfonylureas or placebo, and those reporting changes in BMD and/or bone turnover markers. The primary outcome was percentage change in BMD from baseline and results were pooled with random effects meta-analyses. RESULTS: In all, 18 trials were included in the primary analyses and another two were included in the sensitivity analyses (n = 3,743, 50% women, mean age 56 years, median trial duration 48 weeks). TZDs decreased BMD at the lumbar spine (difference -1.1% [95% CI -1.6, -0.7]; p < 0.0001), total hip (-1.0% [-1.4, -0.6]; p < 0.0001) and forearm (-0.9% [-1.6, -0.3]; p = 0.007). There were statistically non-significant decreases in BMD at the femoral neck (-0.7% [-1.4, 0.0]; p = 0.06) and total body (-0.3% [-0.5, 0.0]; p = 0.08). Five trials (n = 450) showed no statistically significant difference in percentage change in BMD between the TZD group and controls up to 1 year following TZD withdrawal. In 14 trials, the effect of TZD treatment on turnover markers varied considerably between individual studies. CONCLUSIONS/INTERPRETATION: Treatment with TZDs results in modest bone loss that may not be reversed 1 year after cessation of treatment.

Cardiovascular complications of calcium supplements.

There is longstanding concern that calcium supplements might increase cardiovascular risk in patients with renal impairment. The Auckland Calcium Study suggested that the same problem occurs in older people taking these supplements for prevention of osteoporosis. Our subsequent meta-analyses, (which followed protocols finalized before the data was available) confirmed that calcium supplements, with or without vitamin D, adversely affected risk of myocardial infarction and, possibly, stroke. Several groups have re-visited these data, consistently finding an adverse effect of calcium on myocardial infarction, not always statistically significant because some meta-analyses have been under-powered. Whether or not an adverse effect of calcium plus vitamin D on myocardial infarction is found depends on whether two specific groups of subjects are included-those in the Women's Health Initiative who were already taking calcium at the time of randomization, and subjects from an open, cluster-randomized study in which baseline cardiovascular risk was different between groups. Vitamin D alone does not affect vascular risk, so it is unlikely that differences between calcium alone and calcium plus vitamin D are real, and they are more likely to result from the inclusion of studies at high risk of bias. The mechanisms of the adverse cardiovascular effects are uncertain but may be mediated by the increase in serum calcium following supplement ingestion, and the effects of this on vascular function and coagulation. Available evidence suggests the risks of calcium supplements outweigh any small benefits on fracture incidence, so the case for their use is weak.

Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis.

BACKGROUND: Findings from recent meta-analyses of vitamin D supplementation without co-administration of calcium have not shown fracture prevention, possibly because of insufficient power or inappropriate doses, or because the intervention was not targeted to deficient populations. Despite these data, almost half of older adults (older than 50 years) continue to use these supplements. Bone mineral density can be used to detect biologically significant effects in much smaller cohorts. We investigated whether vitamin D supplementation affects bone mineral density. METHODS: We searched Web of Science, Embase, and the Cochrane Database, from inception to July 8, 2012, for trials assessing the effects of vitamin D (D3 or D2, but not vitamin D metabolites) on bone mineral density. We included all randomised trials comparing interventions that differed only in vitamin D content, and which included adults (average age >20 years) without other metabolic bone diseases. We pooled data with a random effects meta-analysis with weighted mean differences and 95% CIs reported. To assess heterogeneity in results of individual studies, we used Cochran's Q statistic and the I(2) statistic. The primary endpoint was the percentage change in bone mineral density from baseline. FINDINGS: Of 3930 citations identified by the search strategy, 23 studies (mean duration 23·5 months, comprising 4082 participants, 92% women, average age 59 years) met the inclusion criteria. 19 studies had mainly white populations. Mean baseline serum 25-hydroxyvitamin D concentration was less than 50 nmol/L in eight studies (n=1791). In ten studies (n=2294), individuals were given vitamin D doses less than 800 IU per day. Bone mineral density was measured at one to five sites (lumbar spine, femoral neck, total hip, trochanter, total body, or forearm) in each study, so 70 tests of statistical significance were done across the studies. There were six findings of significant benefit, two of significant detriment, and the rest were non-significant. Only one study showed benefit at more than one site. Results of our meta-analysis showed a small benefit at the femoral neck (weighted mean difference 0·8%, 95% CI 0·2-1·4) with heterogeneity among trials (I(2)=67%, p<0·00027). No effect at any other site was reported, including the total hip. We recorded a bias toward positive results at the femoral neck and total hip. INTERPRETATION: Continuing widespread use of vitamin D for osteoporosis prevention in community-dwelling adults without specific risk factors for vitamin D deficiency seems to be inappropriate. FUNDING: Health Research Council of New Zealand.

Republished: Paget's disease of bone: clinical review and update.

Paget's disease (PD) is a focal disorder of bone remodelling that occurs commonly in older people. In this article, we review clinical aspects of PD with an emphasis on recent findings. The epidemiology of PD appears to be changing rapidly, with several groups in different parts of the world reporting a marked reduction in the prevalence and incidence of PD, as well as in the severity of disease seen by clinicians. These findings seem most likely to be caused by changes in exposure to unknown environmental factors that have a role in the development of PD. However, genetic factors are also important. Mutations in SQSTM1 occur in 25-50% of familial PD. Genotype-phenotype relationships are present, as PD develops at an earlier age and is more extensive and severe in those with SQSTM1 mutations, and these findings are more pronounced in those with truncating mutations. However, the prevalence of PD in adults with SQSTM1 mutations is uncertain, and it is not known how such mutations might cause PD. Ultimately, if the cause of PD is determined, it seems likely that it will include both genetic and environmental factors. Lastly, clinical trials have shown that potent bisphosphonates are highly effective treatments for active PD, and reduce pain, improve quality of life, normalise bone turnover and heal lytic lesions on radiographs. They can also induce sustained remission that persists for many years.