"Pregnancy and Lactation Associated Osteoporosis".

Pregnancy-associated osteoporosis (PAO) is a rare condition of skeletal fragility affecting women in pregnancy or the postpartum period. During normal pregnancy and lactation, substantial changes in calcium metabolism and skeletal physiology occur in order to meet the demands of the developing foetus. Whilst these adaptations are reversible and generally of no clinical consequence for the mother, a small number of women will develop osteoporosis and suffer fragility fractures. Vertebral fractures occur most commonly in PAO and are often multiple. Due to the rarity of PAO, systematic study to date has been limited. Aetiology is poorly understood, but traditional osteoporosis risk factors and genetic factors are likely to play a role. A small number of cases may be due to an underlying metabolic bone disorder or monogenic condition. Management of PAO is challenging, due both to a poor evidence base and the fact that spontaneous improvement in BMD is known to occur once pregnancy and lactation are complete. Bisphosphonates, denosumab and teriparatide have all been used in individual patients, but the data supporting their use are currently limited.

An online clinical decision tool to screen for vertebral fragility fractures (Vfrac) in older women presenting with back pain in general practice: protocol for a feasibility study in preparation for a future cluster randomised controlled trial.

This feasibility study for a future definitive randomized trial assesses the use and acceptability of a new clinical decision tool to identify risk of a vertebral fracture and those who should be referred for spinal radiography in women aged 65 or over presenting to primary care with back pain. PURPOSE: Approximately 12% of older adults have vertebral fragility fractures, but currently fewer than one-third are diagnosed, potentially limiting access to bone protection treatment. Vfrac is a vertebral fracture screening tool which classifies individuals into high or low risk of having a vertebral fracture, allowing targeting of spinal radiographs to high-risk individuals. The objective of this study was to investigate the feasibility of conducting a cluster randomized controlled trial to evaluate the use of an online version of Vfrac in primary care. METHODS: The study will run in six general practices, with three given the Vfrac tool for use on older women (> 65 years) consulting with back pain and three using standard clinical processes for managing such back pain. Anonymised data covering a 12-month period will be collected from all sites on consultations by older women with back pain. Focus groups will be undertaken with healthcare professionals and patients on whom the tool was used to understand the acceptability of Vfrac and identify factors that impact its use. These patients will be sent a paper version of the Vfrac questionnaire to self-complete at home. Outputs of the self-completion Vfrac (high versus low risk) will be compared with the face-to-face Vfrac (high versus low risk), and agreement assessed using Cohen's kappa. RESULTS: This study will evaluate the use and acceptability of Vfrac within primary care and determine if data on resource use can be collected accurately and comprehensively. CONCLUSIONS: This article describes the protocol of the Vfrac feasibility study. TRIAL REGISTRATION: ISRCTN18000119 (registered 01/03/2022) and ISRCTN12150779 (registered 10/01/2022).

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.

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.

Increased development of radiographic hip osteoarthritis in individuals with high bone mass: a prospective cohort study.

BACKGROUND: Individuals with high bone mass (HBM) have a greater odds of prevalent radiographic hip osteoarthritis (OA), reflecting an association with bone-forming OA sub-phenotypes (e.g. osteophytosis, subchondral sclerosis). As the role of bone mineral density (BMD) in hip OA progression is unclear, we aimed to determine if individuals with HBM have increased incidence and/or progression of bone-forming OA sub-phenotypes. METHODS: We analysed an adult cohort with and without HBM (L1 and/or total hip BMD Z-score > + 3.2) with pelvic radiographs collected at baseline and 8-year follow-up. Sub-phenotypes were graded using the OARSI atlas. Superior/inferior acetabular/femoral osteophyte and medial/superior joint space narrowing (JSN) grades were summed and Δosteophyte and ΔJSN derived. Pain and functional limitations were quantified using the WOMAC questionnaire. Associations between HBM status and change in OA sub-phenotypes were determined using multivariable linear/logistic regression, adjusting for age, sex, height, total body fat mass, follow-up time and baseline sub-phenotype grade. Generalised estimating equations accounted for individual-level clustering. RESULTS: Of 136 individuals, 62% had HBM at baseline, 72% were female and mean (SD) age was 59 (10) years. HBM was positively associated with both Δosteophytes and ΔJSN (adjusted mean grade differences between individuals with and without HBM ßosteophyte = 0.30 [0.01, 0.58], p = 0.019 and ßJSN = 0.10 [0.01, 0.18], p = 0.019). Incident subchondral sclerosis was rare. HBM individuals had higher WOMAC hip functional limitation scores (ß = 8.3 [0.7, 15.98], p = 0.032). CONCLUSIONS: HBM is associated with the worsening of hip osteophytes and JSN over an average of 8 years, as well as increased hip pain and functional limitation.

Mutations in Known Monogenic High Bone Mass Loci Only Explain a Small Proportion of High Bone Mass Cases.

High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52-kb intronic deletion 3'). Family members were assessed for HBM segregation with identified variants. Three-dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (∼prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non-LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5-HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST-LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z-scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z-scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small proportion (∼3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance.

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.

LRP5 regulates human body fat distribution by modulating adipose progenitor biology in a dose- and depot-specific fashion.

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 ß-catenin signaling and led to distinct biological outcomes: diminished gluteal and enhanced abdominal adipogenesis. These data highlight how depot differences in WNT/ß-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.

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 ß [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).

Osteophytes, enthesophytes, and high bone mass: a bone-forming triad with potential relevance in osteoarthritis.

OBJECTIVE: 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. METHODS: Cases of HBM (defined according to bone mineral density [BMD] Z scores on dual x-ray absorptiometry) from the UK-based HBM study were compared with a control group comprising unaffected family members and general population controls from the Chingford and Hertfordshire cohort studies. Pelvic radiographs from cases and controls were pooled and evaluated, in a blinded manner, by a single observer, who performed semiquantitative grading of the radiographs for the presence and severity of osteophytes and enthesophytes (score range 0-3 for each). Logistic regression analysis was used to identify significant associations, with a priori adjustment for age, sex, and body mass index. RESULTS: In this study, 226 radiographs from HBM cases and 437 radiographs from control subjects were included. Enthesophytes (grade ≥1) and moderate enthesophytes (grade ≥2) were more prevalent in HBM cases compared with controls (adjusted odds ratio [OR] 3.00 [95% confidence interval (95% CI) 1.96-4.58], P < 0.001 for any enthesophyte; adjusted OR 4.33 [95% CI 2.67-7.02], P < 0.001 for moderate enthesophytes). In the combined population of cases and controls, the enthesophyte grade was positively associated with BMD at both the total hip and lumbar spine (adjusted P for trend < 0.001). In addition, a positive association between osteophytes and enthesophytes was observed; for each unit increase in enthesophyte grade, the odds of any osteophyte being present were increased >2-fold (P < 0.001). CONCLUSION: Strong interrelationships were observed between osteophytes, enthesophytes, and HBM, which may be helpful in defining a distinct subset of patients with osteoarthritis characterized by excess bone formation.