Sarah A. Hardcastle

Friend or foe: high bone mineral density on routine bone density scanning, a review of causes and management

A finding of high BMD on routine DXA scanning is not infrequent and most commonly reflects degenerative disease. However, BMD increases may also arise secondary to a range of underlying disorders affecting the skeleton. Although low BMD increases fracture risk, the converse may not hold for high BMD, since elevated BMD may occur in conditions where fracture risk is increased, unaffected or reduced. Here we outline a classification for the causes of raised BMD, based on identification of focal or generalized BMD changes, and discuss an approach to guide appropriate investigation by clinicians after careful interpretation of DXA scan findings within the context of the clinical history. We will also review the mild skeletal dysplasia associated with the currently unexplained high bone mass phenotype and discuss recent advances in osteoporosis therapies arising from improved understanding of rare inherited high BMD disorders.

LRP5 Regulates Human Body Fat Distribution by Modulating Adipose Progenitor Biology in a Dose- and Depot-Specific Fashion

Summary Common variants in WNT pathway genes have been associated with bone mass and fat distribution, the latter predicting diabetes and cardiovascular disease risk. Rare mutations in the WNT co-receptors LRP5 and LRP6 are similarly associated with bone and cardiometabolic disorders. We investigated the role of LRP5 in human adipose tissue. Subjects with gain-of-function LRP5 mutations and high bone mass had enhanced lower-body fat accumulation. Reciprocally, a low bone mineral density-associated common LRP5 allele correlated with increased abdominal adiposity. Ex vivo LRP5 expression was higher in abdominal versus gluteal adipocyte progenitors. Equivalent knockdown of LRP5 in both progenitor types dose-dependently impaired β-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/β-catenin pathway activity modulate human fat distribution via effects on adipocyte progenitor biology. They also identify LRP5 as a potential pharmacologic target for the treatment of cardiometabolic disorders.

Individuals with high bone mass have an increased prevalence of radiographic knee osteoarthritis

We previously reported an association between high bone mass (HBM) and a bone-forming phenotype of radiographic hip osteoarthritis (OA). As knee and hip OA have distinct risk factors, in this study we aimed to determine (i) whether HBM is also associated with knee OA, and (ii) whether the HBM knee OA phenotype demonstrates a similar pattern of radiographic features to that observed at the hip. HBM cases (defined by DXA BMD Z-scores) from the UK-based HBM study were compared with unaffected family controls and general population controls from the Chingford and Hertfordshire cohort studies. A single blinded observer graded AP weight-bearing knee radiographs for features of OA (Kellgren–Lawrence score, osteophytes, joint space narrowing (JSN), sclerosis) using an atlas. Analyses used logistic regression, adjusting a priori for age and gender, and additionally for BMI as a potential mediator of the HBM–OA association, using Stata v12. 609 HBM knees in 311 cases (mean age 60.8 years, 74% female) and 1937 control knees in 991 controls (63.4 years, 81% female) were analysed. The prevalence of radiographic knee OA, defined as Kellgren–Lawrence grade ≥ 2, was increased in cases (31.5% vs. 20.9%), with age and gender adjusted OR [95% CI] 2.38 [1.81, 3.14], p < 0.001. The association between HBM and osteophytosis was stronger than that for JSN, both before and after adjustment for BMI which attenuated the ORs for knee OA and osteophytes in cases vs. controls by approximately 50%. Our findings support a positive association between HBM and knee OA. This association was strongest for osteophytes, suggesting HBM confers a general predisposition to a subtype of OA characterised by increased bone formation.

Prevalence of radiographic hip osteoarthritis is increased in high bone mass.

Summary Objective Epidemiological studies have shown an association between increased bone mineral density (BMD) and osteoarthritis (OA), but whether this represents cause or effect remains unclear. In this study, we used a novel approach to investigate this question, determining whether individuals with High Bone Mass (HBM) have a higher prevalence of radiographic hip OA compared with controls. Design HBM cases came from the UK-based HBM study: HBM was defined by BMD Z-score. Unaffected relatives of index cases were recruited as family controls. Age-stratified random sampling was used to select further population controls from the Chingford and Hertfordshire cohort studies. Pelvic radiographs were pooled and assessed by a single observer blinded to case-control status. Analyses used logistic regression, adjusted for age, gender and body mass index (BMI). Results 530 HBM hips in 272 cases (mean age 62.9 years, 74% female) and 1702 control hips in 863 controls (mean age 64.8 years, 84% female) were analysed. The prevalence of radiographic OA, defined as Croft score ≥3, was higher in cases compared with controls (20.0% vs 13.6%), with adjusted odds ratio (OR) [95% CI] 1.52 [1.09, 2.11], P = 0.013. Osteophytes (OR 2.12 [1.61, 2.79], P < 0.001) and subchondral sclerosis (OR 2.78 [1.49, 5.18], P = 0.001) were more prevalent in cases. However, no difference in the prevalence of joint space narrowing (JSN) was seen (OR 0.97 [0.72, 1.33], P = 0.869). Conclusions An increased prevalence of radiographic hip OA and osteophytosis was observed in HBM cases compared with controls, in keeping with a positive association between HBM and OA and suggesting that OA in HBM has a hypertrophic phenotype.

Jump Power and Force Have Distinct Associations With Cortical Bone Parameters: Findings From a Population Enriched by Individuals With High Bone Mass

Context: Little is known of the relationships between muscle function and bone, based on the recently developed technique of jumping mechanography. Objective: Our objective was to determine associations between peak ground reaction force and peak power during a 1-legged hopping test and a single 2-legged jump, respectively, and cortical bone parameters. Design and Setting: This was a cross-sectional observational study in participants from the high bone mass cohort. Participants: Participants included 70 males (mean age 58 years) and 119 females (mean age 56 years); high bone mass cases and controls were pooled. Main Outcome Measures: Total hip bone mineral density (BMD) (measured by dual-energy x-ray absorptiometry scanning) and mid-tibial peripheral quantitative computed tomography (Stratec XCT2000L). Results: Jump power was positively related to hip BMD (standardized β [95% confidence interval] = 0.29 [0.07, 0.51], P = .01), but hopping force was not (0.03 [−0.16, 0.22], P = .74) (linear regression analysis adjusted for age, gender, height, and weight). In 113 participants with force and peripheral quantitative computed tomography data, both jump power and hopping force were positively associated with tibial strength strain index (0.26 [0.09, 0.44], P < .01; and 0.24 [0.07, 0.42], P = .01 respectively). Although hopping force was positively associated with bone size (total bone area 0.22 [0.03, 0.42], P = .02), jump power was not (0.10 [−0.10, 0.30], P = .33). In contrast, jump power was inversely associated with endocortical circumference adjusted for periosteal circumference (−0.24 [−0.40, −0.08], P < .01) whereas no association was seen for hopping force (−0.10 [−0.26, 0.07], P = .24). Conclusions: Although power and force are both positively associated with cortical bone strength, distinct mechanisms appear to be involved because power was primarily associated with reduced endocortical expansion (reflected by endocortical circumference adjusted for periosteal circumference, and hip BMD), whereas force was associated with increased periosteal expansion (reflected by total bone area).

Osteoarthritis and bone mineral density: are strong bones bad for joints?

Osteoarthritis (OA) is a common and disabling joint disorder affecting millions of people worldwide. In OA, pathological changes are seen in all of the joint tissues including bone. Although both cross-sectional and longitudinal epidemiological studies have consistently demonstrated an association between higher bone mineral density (BMD) and OA, suggesting that increased BMD is a risk factor for OA, the mechanisms underlying this observation remain unclear. Recently, novel approaches to examining the BMD-OA relationship have included studying the disease in individuals with extreme high bone mass, and analyses searching for genetic variants associated with both BMD variation and OA, suggesting possible pleiotropic effects on bone mass and OA risk. These studies have yielded valuable insights into potentially relevant pathways that might one day be exploited therapeutically. Although animal models have suggested that drugs reducing bone turnover (antiresorptives) may retard OA progression, it remains to be seen whether this approach will prove to be useful in human OA. Identifying individuals with a phenotype of OA predominantly driven by increased bone formation could help improve the overall response to these treatments. This review aims to summarise current knowledge regarding the complex relationship between BMD and OA.

High bone mass is associated with an increased prevalence of joint replacement: a case–control study

Objective. Epidemiological studies have shown an association between OA and increased BMD. To explore the nature of this relationship, we examined whether the risk of OA is increased in individuals with high bone mass (HBM), in whom BMD is assumed to be elevated due to a primary genetic cause. Methods. A total of 335 115 DXA scans were screened to identify HBM index cases (defined by DXA scan as an L1 Z-score of ≥+3.2 and total hip Z-score ≥+1.2, or total hip Z-score ≥+3.2 and L1 Z-score ≥+1.2). In relatives, the definition of HBM was L1 Z-score plus total hip Z-score ≥+3.2. Controls comprised unaffected relatives and spouses. Clinical indicators of OA were determined by structured assessment. Analyses used logistic regression adjusting for age, gender, BMI and social deprivation. Results. A total of 353 HBM cases (mean age 61.7 years, 77% female) and 197 controls (mean age 54.1 years, 47% female) were included. Adjusted NSAID use was more prevalent in HBM cases versus controls [odds ratio (OR) 2.17 (95% CI 1.10, 4.28); P = 0.03]. The prevalence of joint replacement was higher in HBM cases (13.0%) than controls (4.1%), with an adjusted OR of 2.42 (95% CI 1.06, 5.56); P = 0.04. Adjusted prevalence of joint pain and knee crepitus did not differ between cases and controls. Conclusion. HBM is associated with increased prevalence of joint replacement surgery and NSAID use compared with unaffected controls.

Atypical psoriasis following rituximab for rheumatoid arthritis.

To the Editor: Rituximab (RTX) is a chimeric B cell-depleting monoclonal antibody used in the treatment of non-Hodgkin’s lymphoma and rheumatoid arthritis (RA), and with an emerging role in connective tissue disease therapy. Its use has rarely been associated with skin reactions, in particular psoriasiform skin lesions. We report a case of atypical psoriasis reactivation in a patient with RA following RTX, and we review the literature. A 49-year-old woman presented in 1999 with a seronegative polyarthritis affecting the hands, elbows, feet, hips, and knees. At the time she gave no history of psoriasis. Over the next 10 years she received several disease-modifying antirheumatic drugs (DMARD) sequentially and in combination including sulfasalazine, hydroxychloroquine, methotrexate, azathioprine, gold, and leflunomide. Disease activity persisted, although radiographs remained nonerosive. Her 28-joint Disease Activity Score (DAS28) in September 2010 was 6.45 despite triple DMARD therapy, and she was assessed for a biologic. RTX was chosen in preference to anti-tumor necrosis factor (TNF) treatment because of recurrent shingles and a previous positive Heaf test (chest radiograph normal, quantiferon test negative). In November 2010 … Address correspondence to Dr. S.A. Hardcastle, Department of Rheumatology, Osprey Unit, The Great Western Hospital, Marlborough Road, Swindon SN3 6BB, UK. E-mail: Sarah.Hardcastle{at}bristol.ac.uk

Osteophytes, Enthesophytes, and High Bone Mass: A Bone-Forming Triad With Potential Relevance in Osteoarthritis

Previous studies of skeletal remains have suggested that both enthesophytes and osteophytes are manifestations of an underlying bone‐forming tendency. A greater prevalence of osteophytes has been observed among individuals with high bone mass (HBM) compared with controls. This study was undertaken to examine the possible interrelationships between bone mass, enthesophytes, and osteophytes in a population of individuals with extreme HBM.

High Bone Mass is associated with bone-forming features of osteoarthritis in non-weight bearing joints independent of body mass index

Objectives High Bone Mass (HBM) is associated with (a) radiographic knee osteoarthritis (OA), partly mediated by increased BMI, and (b) pelvic enthesophytes and hip osteophytes, suggestive of a bone-forming phenotype. We aimed to establish whether HBM is associated with radiographic features of OA in non-weight-bearing (hand) joints, and whether such OA demonstrates a bone-forming phenotype. Methods HBM cases (BMD Z-scores ≥ + 3.2) were compared with family controls. A blinded assessor graded all PA hand radiographs for: osteophytes (0–3), joint space narrowing (JSN) (0–3), subchondral sclerosis (0–1), at the index Distal Interphalangeal Joint (DIPJ) and 1st Carpometacarpal Joint (CMCJ), using an established atlas. Analyses used a random effects logistic regression model, adjusting a priori for age and gender. Mediating roles of BMI and bone turnover markers (BTMs) were explored by further adjustment. Results 314 HBM cases (mean age 61.1 years, 74% female) and 183 controls (54.3 years, 46% female) were included. Osteophytes (grade ≥ 1) were more common in HBM (DIPJ: 67% vs. 45%, CMCJ: 69% vs. 50%), with adjusted OR [95% CI] 1.82 [1.11, 2.97], p = 0.017 and 1.89 [1.19, 3.01], p = 0.007 respectively; no differences were seen in JSN. Further adjustment for BMI failed to attenuate ORs for osteophytes in HBM cases vs. controls; DIPJ 1.72 [1.05, 2.83], p = 0.032, CMCJ 1.76 [1.00, 3.06], p = 0.049. Adjustment for BTMs (concentrations lower amongst HBM cases) did not attenuate ORs. Conclusions HBM is positively associated with OA in non-weight-bearing joints, independent of BMI. HBM-associated OA is characterised by osteophytes, consistent with a bone-forming phenotype, rather than JSN reflecting cartilage loss. Systemic factors (e.g. genetic architecture) which govern HBM may also increase bone-forming OA risk.