The Cost of Osteoporosis, Osteopenia, and Associated Fractures in Australia in 2017.

Osteoporosis and osteopenia are increasingly prevalent conditions among older adults. Not only do the fractures associated with poor bone health have significant health consequences for the individual, but also their economic impact is placing increasing financial burden on governments and society. This study aimed to determine the direct economic cost of osteoporosis, osteopenia, and fractures among Australians aged 50 years and older in 2017. This study uses previous Australian data on the incidence and prevalence of osteoporosis and osteopenia together with recent Australian data on health service utilization after fracture to provide an estimate of the economic burden of osteoporosis. A bottom-up costing approach was used to determine the average direct health care and non-health care total costs of a fracture, as well as the average community health service costs of managing individuals with osteoporosis or osteopenia. The total direct cost of osteoporosis in Australia in 2017 was estimated to be $3.44 billion (AUD 2017, USD 2.77 billion). Treatment of fractures accounted for 68% of total direct costs, and non-fracture management of osteoporosis accounted for 32%. Hip fractures accounted for the highest proportion (43%) of the total direct cost of fractures, although fractures at "other" sites accounted for 38.5%. Fractures among individuals aged 70 years and older accounted for 74% of the direct costs (55% and 19% in women and men, respectively). Fracture costs in those with osteopenia accounted for 50% of direct fracture treatment costs. This up-to-date cost analysis estimated that costs in 2017 were three times higher than in 2007. These estimates will aid clinicians, policy makers, researchers, and health care organizations to acknowledge the economic importance of reducing osteoporosis-related fractures and associated costs. This provides a strong public health case to promote bone health that will assist in reducing future fracture-related costs. © 2018 American Society for Bone and Mineral Research.

The Association Between Anxiety and Falls: A Meta-Analysis.

OBJECTIVES: Falls occur frequently among older adults and can lead to a range of adverse and debilitating outcomes. Although symptoms of clinical anxiety have been implicated as risk factors for falls, there is no current consensus on the empirical association between anxiety and falls. The current study aimed to address this gap in the literature by conducting a quantitative, meta-analytic review of findings from previous studies. METHOD: A systematic literature search of bibliographic databases was conducted, yielding 18 studies that fit the criteria for inclusion in the meta-analysis. RESULTS: A random-effects model of all 18 studies showed a significant overall odds ratio of 1.53 (95% CI 1.28-1.83, p < .001), indicating that elevated levels of anxiety were associated with a 53% increased likelihood of falls. A high amount of variance among effect sizes was observed. Only age was identified as a moderator of this relationship in a subgroup of the samples. CONCLUSIONS: Clinical anxiety is associated with falls, however, further research is required to elucidate the factors that might moderate or mediate this relationship, the casual pathways through which they are related, and the associations between different types of anxiety and falls.

Validity of 12-Month Falls Recall in Community-Dwelling Older Women Participating in a Clinical Trial.

Objectives. To compare 12-month falls recall with falls reported prospectively on daily falls calendars in a clinical trial of women aged ≥70 years. Methods. 2,096 community-dwelling women at high risk of falls and/or fracture completed a daily falls calendar and standardised interviews when falls were recorded, for 12 months. Data were compared to a 12-month falls recall question that categorised falls status as "no falls," "a few times," "several," and "regular" falls. Results. 898 (43%) participants reported a fall on daily falls calendars of whom 692 (77%) recalled fall(s) at 12 months. Participants who did not recall a fall were older (median 79.3 years versus 77.8 years, P = 0.028). Smaller proportions of fallers who sustained an injury or accessed health care failed to recall a fall (all P < 0.04). Among participants who recalled "no fall," 85% reported zero falls on daily calendars. Few women selected falls categories of "several times" or "regular" (4.1% and 0.4%, resp.) and the sensitivity of these categories was low (30% to 33%). Simply categorising participants into fallers or nonfallers had 77% sensitivity and 94% specificity. Conclusion. For studies where intensive ascertainment of falls is not feasible, 12-month falls recall questions with fewer responses may be an acceptable alternative.

Changes in gait performance over several years are associated with recurrent falls status in community-dwelling older women at high risk of fracture.

BACKGROUND: Gait analysis is a recommended geriatric assessment for falls risk and sarcopenia; however, previous research utilises measurements at a single time point only. It is presently unclear how changes in gait over several years influence risk of recurrent falls in older adults. METHODS: We investigated 135 female volunteers (mean age±SD: 76.7±5.0 years; range: 70-92 years) at high risk of fracture. Gait parameters (speed, cadence, step length, step width, swing time and double support phase) were assessed using the GAITRite Electronic Walkway System at four annual clinics over ∼3.7±0.5 years. Participants reported incident falls monthly for 3.7±1.2 years. RESULTS: Increasing gait speed (odds ratio: 0.96; 95% confidence interval 0.93, 0.99) and step length (0.87; 0.77, 0.98) from baseline to final follow-up was associated with reduced likelihood of being a recurrent faller over the study period. No significant associations were observed for baseline gait parameters (all P≥0.05). At the second follow-up (2.8±0.6 years), an increase in swing time (0.65; 0.43, 0.98) was associated with reduced likelihood, while an increase in double support phase (1.31; 1.04, 1.66) was associated with increased likelihood, for being a recurrent faller in the subsequent 1.3 years following this time point. CONCLUSION: Changes in gait parameters over several years are significantly associated with the likelihood of being a recurrent faller among community-dwelling older women at high risk of fracture. Further research is required to develop gait monitoring guidelines and gait parameter decline cut points that may be utilised by clinicians to identify older adults at risk of incident falls and sarcopenia.

Investigating the predictive ability of gait speed and quadriceps strength for incident falls in community-dwelling older women at high risk of fracture.

Gait speed is a recommended geriatric assessment of physical performance, but may not be regularly examined in clinical settings. We aimed to investigate whether quadriceps strength tests demonstrate similar predictive ability for incident falls as gait speed in older women. We investigated 135 female volunteers aged mean±SD 76.7±5.0 years (range 70-92) at high risk of fracture. Participants completed gait speed assessments using the GAITRite Electronic Walkway System, and quadriceps strength assessments using a hand-held dynamometer (HHD). Participants reported incident falls monthly for 3.7±1.2 years. N=99 (73%) participants fell 355 times during the follow-up period (mean fall rate 83 per 100 person years). We observed a reduced odds ratio for multiple falls (0.83, 95% CI 0.70-0.98) and a reduced hazard ratio for time to first fall (0.90, 95% CI 0.83-0.98), according to quadriceps strength. There was also a significantly shorter time to first fall for those with low quadriceps strength (<7.0 kg; lowest tertile) compared with those with normal quadriceps strength (estimated means [95% CI] 1.54 [1.02, 2.06] vs. 2.23 [1.82, 2.64] years; P=0.019), but not for those with low (<1.0 m/s) vs. normal gait speed (P=0.15). Quadriceps strength is a significant predictor of incident falls over three years amongst community-dwelling older women at high risk of fracture. Quadriceps strength tests may be an acceptable alternative to gait speed for geriatric assessments of falls risk.

Dominant negative MCP-1 blocks human osteoclast differentiation.

Human osteoclasts were differentiated using receptor activator of NFκB ligand (RANKL) and macrophage colony stimulating factor (M-CSF) from colony forming unit-granulocyte macrophage (CFU-GM) precursors of the myeloid lineage grown from umbilical cord blood. Gene expression profiling using quantitative polymerase chain reaction (Q-PCR) showed more than 1,000-fold induction of chemokine MCP-1 within 24 h of RANKL treatment. MCP-1 mRNA content exceeds that of other assayed chemokines (CCL1, 3, 4, and 5) at all time points up to day 14 of treatment. MCP-1 induction preceded peak induction of calcium signaling activator calmodulin 1 (CALM1) and transcription factors JUN and FOS, which were at 3 days. Key osteoclast related transcription factors NFATc1 and NFATc2 showed peak induction at 7 days, while marker genes for osteoclast function cathepsin K and tartrate resistance acid phosphatase (TRAP) were maximally induced at 14 days, corresponding with mature osteoclast function. To test whether the early and substantial peak in MCP-1 expression is part of human osteoclast differentiation events, a dominant negative inhibitor of MCP-1 (7ND) was added simultaneously with RANKL and M-CSF, resulting in blockade of CALM1, JUN and NFATc2 induction and strong inhibition of human osteoclast differentiation. These data show that a cascade of gene expression leading to osteoclast differentiation depends on intact early MCP-1 induction and signaling in human osteoclasts.

Musculoskeletal deterioration in men accompanies increases in body fat.

OBJECTIVE: To examine body fat and musculoskeletal changes in men over 5 years. METHODS: Body composition was evaluated for men in the Geelong Osteoporosis Study using whole body dual energy X-ray absorptiometry (DXA) during two time-periods. DXA was performed for 1329 men (25-96 years) during 2001-2006 and for 900 men (25-98 years), 2006-2011. The masses of fat, lean, and bone were expressed relative to the square of height (kg/m2). Each compartment was also expressed as a percentage relative to body weight (%fat, %lean, %bone). RESULTS: Mean BMI increased from 26.9 kg/m2 in 2001-2006, to 27.2 kg/m2 in 2006-2011 (P = 0.04). Mean fat mass increased by 9.0% from 6.98 kg/m2 (95% CI 6.84-7.11) in 2001-2006, to 7.60 kg/m2 (7.44-7.77) in 2006-2011 (P < 0.001); mean lean mass decreased by 0.9%, from 18.92 kg/m2 (18.83-19.01) to 18.75 kg/m2 (18.64-18.86) (P = 0.02), and mean bone mass decreased 1.6% from 1.041 kg/m2 (1.034-1.047), to 1.024 kg/m2 (1.016-1.032). Mean %fat increased from 23.4% to 25.2%, mean %lean decreased from 72.6% to 70.9% and mean %bone decreased from 4.0% to 3.9% (all P < 0.05). CONCLUSIONS: An increase in BMI, which reflects a substantial increase in body fat mass and declines in both lean and bone mass was reported. This may have implications for future development of bone fragility, sarcopenia, and sarcopenic obesity.

Polyalanine repeat polymorphism in RUNX2 is associated with site-specific fracture in post-menopausal females.

Runt related transcription factor 2 (RUNX2) is a key regulator of osteoblast differentiation. Several variations within the RUNX2 gene have been found to be associated with significant changes in BMD, which is a major risk factor for fracture. In this study we report that an 18 bp deletion within the polyalanine tract (17A>11A) of RUNX2 is significantly associated with fracture. Carriers of the 11A allele were found to be nearly twice as likely to have sustained fracture. Within the fracture category, there was a significant tendency of 11A carriers to present with fractures of distal radius and bones of intramembranous origin compared to bones of endochondral origin (p = 0.0001). In a population of random subjects, the 11A allele was associated with decreased levels of serum collagen cross links (CTx, p = 0.01), suggesting decreased bone turnover. The transactivation function of the 11A allele showed a minor quantitative decrease. Interestingly, we found no effect of the 11A allele on BMD at multiple skeletal sites. These findings suggest that the 11A allele is a biologically relevant polymorphism that influences serum CTx and confers enhanced fracture risk in a site-selective manner related to intramembranous bone ossification.

Glutamine repeat variants in human RUNX2 associated with decreased femoral neck BMD, broadband ultrasound attenuation and target gene transactivation.

RUNX2 is an essential transcription factor required for skeletal development and cartilage formation. Haploinsufficiency of RUNX2 leads to cleidocranial displaysia (CCD) a skeletal disorder characterised by gross dysgenesis of bones particularly those derived from intramembranous bone formation. A notable feature of the RUNX2 protein is the polyglutamine and polyalanine (23Q/17A) domain coded by a repeat sequence. Since none of the known mutations causing CCD characterised to date map in the glutamine repeat region, we hypothesised that Q-repeat mutations may be related to a more subtle bone phenotype. We screened subjects derived from four normal populations for Q-repeat variants. A total of 22 subjects were identified who were heterozygous for a wild type allele and a Q-repeat variant allele: (15Q, 16Q, 18Q and 30Q). Although not every subject had data for all measures, Q-repeat variants had a significant deficit in BMD with an average decrease of 0.7SD measured over 12 BMD-related parameters (p = 0.005). Femoral neck BMD was measured in all subjects (-0.6SD, p = 0.0007). The transactivation function of RUNX2 was determined for 16Q and 30Q alleles using a reporter gene assay. 16Q and 30Q alleles displayed significantly lower transactivation function compared to wild type (23Q). Our analysis has identified novel Q-repeat mutations that occur at a collective frequency of about 0.4%. These mutations significantly alter BMD and display impaired transactivation function, introducing a new class of functionally relevant RUNX2 mutants.

Endogenous parathyroid hormone is associated with reduced cartilage volume in vivo in a population-based sample of adult women.

OBJECTIVES: Animal and in vitro studies suggest that parathyroid hormone (PTH) may affect articular cartilage. However, little is known of the relationship between PTH and human joints in vivo. DESIGN: Longitudinal. SETTING: Barwon Statistical Division, Victoria, Australia. PARTICIPANTS: 101 asymptomatic women aged 35-49 years (2007-2009) and without clinical knee osteoarthritis, selected from the population-based Geelong Osteoporosis Study. RISK FACTORS: Blood samples obtained 10 years before (1994-1997) and stored at -80°C for random batch analyses. Serum intact PTH was quantified by chemiluminescent enzyme assay. Serum 25-hydroxyvitamin D (25(OH)D) was assayed using equilibrium radioimmunoassay. Models were adjusted for age, bone area and body mass index; further adjustment was made for 25(OH)D and calcium supplementation. OUTCOME: Knee cartilage volume, measured by MRI. RESULTS: A higher lnPTH was associated with reduced medial-but not lateral-cartilage volume (regression coefficient±SD, p value: -72.2±33.6 mm(3), p=0.03) after adjustment for age, body mass index and bone area. Further sinusoidal adjustment (-80.8±34.4 mm(3), p=0.02) and 25(OH)D with seasonal adjustment (-72.7±35.1 mm(3), p=0.04), calcium supplementation and prevalent osteophytes did not affect the results. CONCLUSIONS: A higher lnPTH might be detrimental to knee cartilage in vivo. Animal studies suggest that higher PTH concentrations reduce the healing ability of cartilage following minor injury. This may be apparent in the presence of increased loading, which occurs in the medial compartment, placing the medial cartilage at higher risk for injury.

Genome-wide association identifies three new susceptibility loci for Paget's disease of bone.

Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone remodeling. We previously identified variants at the CSF1, OPTN and TNFRSF11A loci as risk factors for PDB by genome-wide association study. Here we extended this study, identified three new loci and confirmed their association with PDB in 2,215 affected individuals (cases) and 4,370 controls from seven independent populations. The new associations were with rs5742915 within PML on 15q24 (odds ratio (OR) = 1.34, P = 1.6 × 10(-14)), rs10498635 within RIN3 on 14q32 (OR = 1.44, P = 2.55 × 10(-11)) and rs4294134 within NUP205 on 7q33 (OR = 1.45, P = 8.45 × 10(-10)). Our data also confirmed the association of TM7SF4 (rs2458413, OR = 1.40, P = 7.38 × 10(-17)) with PDB. These seven loci explained ∼13% of the familial risk of PDB. These studies provide new insights into the genetic architecture and pathophysiology of PDB.

Annual high-dose vitamin D3 and mental well-being: randomised controlled trial.

BACKGROUND: Epidemiological evidence supports a relationship between vitamin D and mental well-being, although evidence from large-scale placebo-controlled intervention trials is lacking. AIMS: To examine if vitamin D supplementation has a beneficial effect on mood in community-dwelling older women; if a single annual large dose of vitamin D has a role in the prevention of depressive symptoms; and if there is an association between serum 25-hydroxyvitamin D levels and mental health. METHOD: A double-blind, randomised, placebo-controlled trial of women aged 70 or older (the Vital D Study: ISRCTN83409867 and ACTR12605000658617). Participants were randomly assigned to receive 500 000 IU vitamin D(3) (cholecalciferol) orally or placebo every autumn/winter for 3-5 consecutive years. The tools utilised at various time points were the General Health Questionnaire, the 12-item Short Form Health Survey, the Patient Global Impression-Improvement scale and the WHO Well-Being Index. Serum 25-hydroxyvitamin D levels were measured in a subset of 102 participants. RESULTS: In this non-clinical population, no significant differences between the vitamin D and placebo groups were detected in any of the measured outcomes of mental health. Serum 25-hydroxyvitamin D levels in the vitamin D group were 41% higher than the placebo group 12 months following their annual dose. Despite this difference, scores from the questionnaires did not differ. Furthermore, there was no interaction between those on antidepressant/anxiety medication at baseline and the treatment groups. CONCLUSIONS: The lack of improvement in indices of mental well-being in the vitamin D group does not support the hypothesis that an annual high dose of vitamin D(3) is a practical intervention to prevent depressive symptoms in older community-dwelling women.

Independent and combined effects of calcium-vitamin D3 and exercise on bone structure and strength in older men: an 18-month factorial design randomized controlled trial.

CONTEXT: Exercise and calcium-vitamin D are independently recognized as important strategies to prevent osteoporosis, but their combined effects on bone strength and its determinants remain uncertain. OBJECTIVE: To assess whether calcium-vitamin D(3) fortified milk could enhance the effects of exercise on bone strength, structure, and mineral density in middle-aged and older men. DESIGN, SETTING, PARTICIPANTS: An 18-month factorial design randomized controlled trial in which 180 men aged 50-79 years were randomized to the following: exercise + fortified milk; exercise; fortified milk; or controls. Exercise consisted of progressive resistance training with weight-bearing impact activities performed 3 d/week. Men assigned to fortified milk consumed 400 ml/d of 1% fat milk containing 1000 mg/d calcium and 800 IU/d vitamin D(3). MAIN OUTCOME MEASURES: Changes in bone mineral density (BMD), bone structure, and strength at the lumbar spine (LS), proximal femur, mid-femur, and mid-tibia measured by dual energy x-ray absorptiometry and/or quantitative computed tomography. RESULTS: There were no exercise-by-fortified milk interactions at any skeletal site. Main effect analysis showed that exercise led to a 2.1% (95% confidence interval, 0.5-3.6) net gain in femoral neck section modulus, which was associated with an approximately 1.9% gain in areal BMD and cross-sectional area. Exercise also improved LS trabecular BMD [net gain 2.2% (95% confidence interval, 0.2-4.1)], but had no effect on mid-femur or mid-tibia BMD, structure, or strength. There were no main effects of the fortified milk at any skeletal site. CONCLUSION: A community-based multi-component exercise program successfully improved LS and femoral neck BMD and strength in healthy older men, but providing additional calcium-vitamin D(3) to these replete men did not enhance the osteogenic response.

Does an increase in body mass index over 10 years affect knee structure in a population-based cohort study of adult women?

INTRODUCTION: Although obesity is a modifiable risk factor for knee osteoarthritis (OA), the effect of weight gain on knee structure in young and healthy adults has not been examined. The aim of this study was to examine the relationship between body mass index (BMI), and change in BMI over the preceding 10-year period, and knee structure (cartilage defects, cartilage volume and bone marrow lesions (BMLs)) in a population-based sample of young to middle-aged females. METHODS: One hundred and forty-two healthy, asymptomatic females (range 30 to 49 years) in the Barwon region of Australia, underwent magnetic resonance imaging (MRI) during 2006 to 2008. BMI measured 10 years prior (1994 to 1997), current BMI and change in BMI (accounting for baseline BMI) over this period, was assessed for an association with cartilage defects and volume, and BMLs. RESULTS: After adjusting for age and tibial plateau area, the risk of BMLs was associated with every increase in one-unit of baseline BMI (OR 1.14 (95% CI 1.03 to 1.26) P = 0.009), current BMI (OR 1.13 (95% CI 1.04 to 1.23) P = 0.005), and per one unit increase in BMI (OR 1.14 (95% CI 1.03 to 1.26) P = 0.01). There was a trend for a one-unit increase in current BMI to be associated with increased risk of cartilage defects (OR 1.06 (95% CI 1.00 to 1.13) P = 0.05), and a suggestion that a one-unit increase in BMI over 10 years may be associated with reduced cartilage volume (-17.8 ml (95% CI -39.4 to 3.9] P = 0.10). Results remained similar after excluding those with osteophytes. CONCLUSIONS: This study provides longitudinal evidence for the importance of avoiding weight gain in women during early to middle adulthood as this is associated with increased risk of BMLs, and trend toward increased tibiofemoral cartilage defects. These changes have been shown to precede increased cartilage loss. Longitudinal studies will show whether avoiding weight gain in early adulthood may play an important role in diminishing the risk of knee OA.

Genome-wide association study identifies variants at CSF1, OPTN and TNFRSF11A as genetic risk factors for Paget's disease of bone.

Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by focal increases in bone turnover, which in some cases is caused by mutations in SQSTM1. To identify additional susceptibility genes, we performed a genome-wide association study in 750 individuals with PDB (cases) without SQSTM1 mutations and 1,002 controls and identified three candidate disease loci, which were then replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 near the CSF1 gene (P = 5.38 x 10(-24)). Significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 x 10(-13)) and with rs3018362 on 18q21 near the TNFRSF11A gene (P = 5.27 x 10(-13)). These studies provide new insights into the pathogenesis of PDB and identify OPTN, CSF1 and TNFRSF11A as candidate genes for disease susceptibility.

Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice.

Effective osteoporosis therapy requires agents that increase the amount and/or quality of bone. Any modification of osteoclast-mediated bone resorption by disease or drug treatment, however, elicits a parallel change in osteoblast-mediated bone formation because the processes are tightly coupled. Anabolic approaches now focus on uncoupling osteoblast action from osteoclast formation, for example, by inhibiting sclerostin, an inhibitor of bone formation that does not influence osteoclast differentiation. Here, we report that oncostatin M (OSM) is produced by osteoblasts and osteocytes in mouse bone and that it has distinct effects when acting through 2 different receptors, OSM receptor (OSMR) and leukemia inhibitory factor receptor (LIFR). Specifically, mouse OSM (mOSM) inhibited sclerostin production in a stromal cell line and in primary murine osteoblast cultures by acting through LIFR. In contrast, when acting through OSMR, mOSM stimulated RANKL production and osteoclast formation. A key role for OSMR in bone turnover was confirmed by the osteopetrotic phenotype of mice lacking OSMR. Furthermore, in contrast to the accepted model, in which mOSM acts only through OSMR, mOSM inhibited sclerostin expression in Osmr-/- osteoblasts and enhanced bone formation in vivo. These data reveal what we believe to be a novel pathway by which bone formation can be stimulated independently of bone resorption and provide new insights into OSMR and LIFR signaling that are relevant to other medical conditions, including cardiovascular and neurodegenerative diseases and cancer.