Non-hip and non-vertebral fractures: the neglected fracture sites

Holloway, Kara L.; Henry, Margaret J.; Brennan-Olsen, Sharon L.; Bucki-Smith, Gosia; Nicholson, Geoffrey C.; Korn, Sam; Sanders, Kerrie M.; Pasco, Julie A.; Kotowicz, Mark A.

doi:10.1007/s00198-015-3322-8

Cited by 16 publications

(7 citation statements)

References 25 publications

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“…5,7,10 NOTUM inhibition stimulates endocortical bone formation, thereby increasing cortical bone strength, and might be useful for preventing non-vertebral fractures. 2,3 Second, as a secreted enzyme that reduces cortical bone thickness NOTUM is a tractable pharmacological target, with orally active small molecule inhibitors or neutralizing antibodies inhibiting its activity and thereby increasing cortical bone thickness. Third, the occurrence of increased bone mass and strength in heterozygous Notum mice indicates that NOTUM inhibition does not need to be complete for a therapeutically significant effect.…”

Section: Discussionmentioning

confidence: 99%

“…1 One of the greatest burdens is attributed to osteoporotic fractures, which have an incidence that increases exponentially with age. Although substantial progress has been made in the therapeutic reduction of vertebral fracture risk in osteoporotic individuals, the risk of non-vertebral fractures, which make a greater contribution to mortality, 2,3 is reduced only marginally by currently available treatments, defining an unmet medical need. 4 Cortical bone, comprising 80% of skeletal mass, is a major determinant of bone strength and non-vertebral fracture susceptibility, and marrow cavity expansion from endocortical bone loss with age is a major contributor to osteoporosis.…”

Section: Introductionmentioning

confidence: 99%

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NOTUM inhibition increases endocortical bone formation and bone strength

et al. 2019

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The disability, mortality and costs caused by non-vertebral osteoporotic fractures are enormous. Existing osteoporosis therapies are highly effective at reducing vertebral but not non-vertebral fractures. Cortical bone is a major determinant of non-vertebral bone strength. To identify novel osteoporosis drug targets, we phenotyped cortical bone of 3 366 viable mouse strains with global knockouts of druggable genes. Cortical bone thickness was substantially elevated in Notum−/− mice. NOTUM is a secreted WNT lipase and we observed high NOTUM expression in cortical bone and osteoblasts but not osteoclasts. Three orally active small molecules and a neutralizing antibody inhibiting NOTUM lipase activity were developed. They increased cortical bone thickness and strength at multiple skeletal sites in both gonadal intact and ovariectomized rodents by stimulating endocortical bone formation. Thus, inhibition of NOTUM activity is a potential novel anabolic therapy for strengthening cortical bone and preventing non-vertebral fractures.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NOTUM inhibition increases endocortical bone formation and bone strength

et al. 2019

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“…This potential association is important because NHNV fractures account for more than 50% of fractures. Compared with hip and vertebral fractures, they receive less attention, possibly because of clinicians’ perception they are not associated with adverse consequences or to difficulties accessing accurate data because they often do not require hospital admission. However, there is increasing evidence that NHNV fractures contribute significantly to the burden of subsequent fractures and increased premature mortality …”

Section: Introductionmentioning

confidence: 99%

Comorbidities Only Account for a Small Proportion of Excess Mortality After Fracture: A Record Linkage Study of Individual Fracture Types

Chen

Simpson

March

et al. 2018

Journal of Bone and Mineral Research

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Nonhip, nonvertebral (NHNV) fractures constitute the majority of osteoporotic fractures, but few studies have examined the association between these fractures, comorbidity, and mortality. Our objective was to examine the relationship between individual nonhip, nonvertebral fractures, comorbidities, and mortality. The prospective population-based cohort of 267,043 subjects (45 and Up Study, Australia) had baseline questionnaires linked to hospital administrative and all-cause mortality data from 2006 to 2013. Associations between fracture and mortality were examined using multivariate, time-dependent Cox models, adjusted for age, prior fracture, body mass index, smoking, and comorbidities (cardiovascular disease, diabetes, stroke, thrombosis, and cancer), and survival function curves. Population attributable fraction was calculated for each level of risk exposure. During 1,490,651 person-years, women and men experienced 7571 and 4571 fractures and 7064 deaths and 11,078 deaths, respectively. In addition to hip and vertebral fractures, pelvis, humerus, clavicle, rib, proximal tibia/fibula, elbow and distal forearm fractures in both sexes, and ankle fractures in men were associated with increased multivariable-adjusted mortality hazard ratios ranging from 1.3 to 3.4. Comorbidity independently added to mortality such that a woman with a humeral fracture and 1 comorbidity had a similarly reduced 5-year survival as that of a woman with a hip fracture and no comorbidities. Population mortality attributable to any fracture without comorbidity was 9.2% in women and 5.3% in men. All proximal nonhip, nonvertebral fractures in women and men were associated with increased mortality risk. Coexistent comorbidities independently further increased mortality. Population attributable risk for mortality for fractures was similar to cardiovascular disease and diabetes, highlighting their importance and potential benefit for early intervention and treatment. © 2018 American Society for Bone and Mineral Research.

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“…Non-hip, nonvertebral fractures are responsible for a greater proportion of fractures than the hip or vertebrae [7,8]. They account for significant detrimental effect on quality of life, long time of hospitalization, rehabilitation, and/or nursing home care [7,9]. Moreover, non-vertebral fractures beyond the hip are also associated with an increased risk of subsequent fracture [10], and they are also an important indicator of the impact of osteoporosis because they are more easily documented than vertebral fractures [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…Even in developed countries, currently available prospective data on incidence of non-vertebral fractures beyond hip are scarce [15,16]. Moreover, studies on nonhip, non-vertebral fractures commonly include those not definitely related to osteoporosis such as ankle, skull, face, elbow, finger, and cervical spine [4,[6][7][8][9]16] and/or subjects less likely to have low bone mass such as those younger than 50 years [6].…”

Section: Introductionmentioning

confidence: 99%

Incidence and risk factors for osteoporotic non-vertebral fracture in low-income community-dwelling elderly: a population-based prospective cohort study in Brazil. The São Paulo Ageing and Health (SPAH) study

et al. 2020

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We ascertained the incidence of non-vertebral fracture in a low-income Brazilian elderly cohort. To the best of our knowledge, this is the first population-based study to demonstrate the frequency of non-vertebral fracture in elderly Latin Americans. Age, prior fracture, and bone mineral density (BMD) at hip were predictors of fracture. Introduction No data on incidence of osteoporotic non-vertebral fracture have been reported in low-income countries where the population's aging has been faster. Even in developed countries, currently available prospective data on major fracture rates beyond hip are scarce. The aim of this study is to describe the incidence and risk factors for non-vertebral fracture in a longitudinal prospective Brazilian population-based elderly cohort. Methods Seven hundred seven older adults (449 women, 258 men) were evaluated at baseline and after a mean follow-up of 4.3 ± 0.8 years. Clinical questionnaire, bone mineral density (BMD), and laboratory tests were performed at baseline. New nonvertebral fracture (hip, proximal humerus, rib, forearm) was determined during the follow-up. Multivariate Poisson regression models were used to identify independent predictors of fracture.

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Non-hip and non-vertebral fractures: the neglected fracture sites

Abstract: Given the high numbers of NHNVF sustained by men and women in this study, fracture prevention strategies should focus on individuals with high risk of sustaining these types of fractures, as well as on individuals who are more likely to sustain a HF or VF.

Cited by 16 publications

References 25 publications

NOTUM inhibition increases endocortical bone formation and bone strength

NOTUM inhibition increases endocortical bone formation and bone strength

Comorbidities Only Account for a Small Proportion of Excess Mortality After Fracture: A Record Linkage Study of Individual Fracture Types

Incidence and risk factors for osteoporotic non-vertebral fracture in low-income community-dwelling elderly: a population-based prospective cohort study in Brazil. The São Paulo Ageing and Health (SPAH) study

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