Osteoporotic fractures and obesity affect frailty progression: a longitudinal analysis of the Canadian multicentre osteoporosis study

The segment of the population aged 60 years or older is the fastest growing. It is expected to double by 2050 (from 901 million in 2015 to 2.1 billion), representing 22% of the global population [1]. However, longevity may not be associated with healthy aging, but with frailty [2, 3]. Frailty results from the accumulation of age-related deficits in different physiological systems and is a clinical state that leads to greater risks of adverse health outcomes, such as falls, fractures, hospitalizations, loss of independence, and death [4‐8]. Several screening tools for frailty have also been validated [9, 10]. However, understanding how frailty progression may be modified remains unclear. Cross-sectional studies have demonstrated the impact of risk factors such as physical activity [6‐8]; but, a gap persists regarding important modifiable and non-modifiable predictors of frailty change over time. We explored the effects of low-trauma fractures, obesity and other modifiable and non-modifiable factors on changes in frailty over time in Canadians aged 50 years and older.

The cohort included 7753 CaMos participants (5566 women) aged 50 years and older. Of these, 6162 participants (4348 women) reported no fractures, and 1574 participants had prior (prevalent) low-trauma fractures (1206 women). Table 1 presents their demographic, anthropometric, and lifestyle characteristics, comorbidities, bone health, HRQL and cognitive status. The mean baseline age (±SD) for all participants was 66.7 ± 9.4 years (women: 66.8 ± 9.3; men: 66.3 ± 9.5); for those without prevalent fractures, it was 66.2 ± 9.3 years, and for those with prior fractures, it was 68.9 ± 9.2 years. Participants aged 80+ comprised 9.0% of the sample without prior fractures and 11.4% of the sample with prior fractures. The mean baseline BMI was 27.1 kg/m² and at least one in five participants was obese (class I to III). Participants expended on average 4160 to 4900 kcal weekly on exercise, the majority including moderate physical activities such as brisk walking. Also, 34% of participants without prior fractures and 41% of those with prior fractures reported up to four comorbidities at baseline. Approximately 20% of the participants used antiresorptives at baseline, and up to 36% used them at year 10.

Over 10 years, 893 incident low-trauma fractures occurred in women and 151 in men (Additional file 2: Table S1). They occurred in 7.4% of participants over the first 5 years (women: 8.7%, men: 3.9%) and in 8.1% of participants over the next 5 years (women: 9.5%; men: 4.2%). About 2.0–2.5% of adults reported new hip or clinical vertebral fractures during 10 years (1%: prevalent fractures). A NHNV fracture was the most frequent (12%: prevalent, reported at baseline; 8%: incident). Among NHNV fractures, wrist or forearm fractures were the most frequent (e.g., 44% of all prevalent fractures). Less than 1% of the sample had incident multiple fractures during 10 years.

The mean baseline CFI (± SD) was 0.14 ± 0.11 in participants without prevalent fractures (women: 0.15 ± 0.11, men: 0.12 ± 0.10). It was higher (0.17 ± 0.12) in those with prior fractures (women: 0.18 ± 0.12, men: 0.13 ± 0.10) (Table 2). Changes in frailty over time appeared to be nonlinear: the mean CFI increased on average by 0.03 ± 0.08 over the first 5 years, but it slightly decreased by 0.02 ± 0.08 in the next 5 years. Frailty progression was the greatest in women aged 65+ and men aged 80+ years (Table 3).

In unadjusted and multivariable-adjusted analyses, the progression of frailty was substantially affected by fracture site (Table 3; Additional file 2: Tables S2-S4; S8-S12). The impact differed between two sexes. In the sample including all participants (Table 3 & Additional file 2: Figure S1), the adjusted mean CFI score significantly increased per 5 years after an incident hip fracture by 0.07 in women (95% confidence interval [CI]: 0.03–0.11) and by 0.12 in men (95% CI: 0.08–0.16). An incident clinical vertebral fracture was associated with a similar 0.05 point increase in the adjusted mean CFI score in women (95% CI: 0.02–0.08), and a much smaller increase in men (0.01, 95% CI: -0.07–0.09). Also, incident multiple fractures had larger detrimental effects on frailty progression in women than in men (0.06, 95% CI: 0.01–0.11 vs. 0.03, 95% CI: -0.05–0.06, Additional file 2: Table S8). In women without prior fracture, incident hip and vertebral fractures increased the adjusted mean CFI scores to similar extents (0.07, 95% CI: 0.01–0.13; 0.06, 95% CI: 0.02–0.10); however, in men, incident hip and NHNV fractures variably affected the progression of frailty, increasing the mean score by 0.11 (95% CI: 0.06–0.16) and 0.05 (95% CI: 0.004–0.096) per 5 years, respectively (Figs 1 and 2; Additional file 2: Table S9). In participants with prior fracture, a new hip fracture was the only low-trauma fracture associated with a significantly faster frailty progression (0.07, 95% CI: 0.01–0.12, Fig. 3 and Additional file 2: Table S11).

Baseline BMI was another important predictor of frailty progression. In both women and men, the higher baseline BMI was associated with a larger impact on frailty (Table 3; Additional file 2: Tables S5-S12). This was pronounced in adults without prior fractures (Additional file 2: Table S9). In multivariable-adjusted models, compared to participants with normal weight, overweight participants had a 5-year increase in the adjusted mean CFI of 0.01, those with obesity class I-II had an increase of 0.02, and those with morbid obesity had increases of 0.01 to 0.10 (Additional file 2: Figure S1, Figs 1, 2 and 3).

In addition to prior and incident fractures and obesity, some other predictors affected the progression of frailty: living alone (men: Additional file 2: Figure S1b and Fig. 2; p < 0.04), use of antiresorptives for 10 years (men: Additional file 2: Figure S1b and Fig. 2; p < 0.005), lower baseline BMD T-scores (Fig. 3; p = 0.02), and unemployment (Fig. 3; p = 0.03). Predictors that decelerated frailty were greater physical activity (women: Additional file 2: Figure S1a, Fig. 1 and both sexes: Fig. 3; p < 0.04), better HRQL (both sexes: Additional file 2: Figure S1, Figs 1-3; p < 0.0001), better cognitive function (women: Additional file 2: Figure S1a and Fig. 1; p < 0.05), university education (men: Additional file 2: Figure S1b; p = 0.04), and low alcohol consumption (women: Additional file 2: Figure S1a; p = 0.03).

Over 10 years, 3411 participants (44%) were lost to follow-up. Compared to participants who remained in the study, they were frailer (mean CFI: 0.18 ± 0.12), older, more often men, more often retired and living alone, more often underweight, less physically active, more often smokers, with prior low-trauma fractures and falls, with lower HRQL and cognitive scores (all p-values < 0.05, Additional file 2: Table S13). As expected, adults who died by year 10 had much greater CFI scores than those who dropped out (Additional file 2: Table S14). Our sensitivity analyses that addressed attrition or missing data bias corroborated the main findings (Additional file 2: Tables S15-S23), and also suggested a protective effect of non-smoking with the corresponding frailty 5-year reduction of 0.01 to 0.03 in the adjusted mean CFI (p < 0.01, Additional file 2: Tables S17-S23).

This study explored which predictors strongly affect the progression or deceleration of frailty over time in a population-based sample including over 7500 Canadian women and men aged 50 years and older. Two modifiable risk factors, incident low-trauma fractures and obesity, consistently increased frailty. Their effects on frailty progression were also clinically plausible because the rates of change were greater than a previously recognized minimal clinically important difference of 0.04 [16]. The long-term effects of low-trauma fractures were different between two sexes and depended on the history of fracture. In women who never had a low-trauma fracture, incident hip and clinical vertebral fractures had a similar impact on the progression of frailty; in contrast, an incident hip fracture was the only osteoporotic fracture associated with frailty progression in men. Prior low-trauma fracture intrinsically implies a different starting state [18]. Thus, individuals with prior fractures had more comorbidities and were frailer at baseline. In this subgroup, irrespective of the sex, an incident hip fracture significantly increased frailty over 10 years. Obesity consistently contributed to frailty progression in both women and men. Compared to normal weight participants (baseline BMI:25.0–29.9 kg/m²), the adjusted mean CFI increased by 0.01 per 5 years in overweight individuals (25.0–29.9 kg/m²) and was at least five times greater in pathologically obese individuals (BMI≥ 40.0 kg/m²). The impact was greater in adults who had no history of fractures and were less frail at baseline. Our analyses also showed that quality of life and physical activity protected against frailty; however, their impact might not be considered clinically meaningful because it is much smaller than the effect of fractures and obesity. Thus, greater HRQL scores suggesting better participants’ perceptions of physical and mental health were associated with decreases in frailty over time. Moreover, achieving a recommended weekly amount of physical activity of 1000 kilocals, which equals to approximately 30 min of walking per day [14, 15], significantly slowed down frailty over time in women without prior fractures and in adults with prior fractures.

Our findings have important public health implications and support hypotheses that frailty has a dynamic nature and may be attenuated through interventions aimed towards prevention and treatment of low-trauma fractures and obesity [4, 5, 7, 19]. Significant increases in the risks of hip and non-vertebral fractures in frail compared with robust populations were found in previous studies [8, 16, 20, 21]. Also, a significant increase of the Frailty Index score by 0.08 was found up to 2 years after a major osteoporotic fracture in frail elderly women with prior fractures (the mean baseline score: 0.24) [20]. Our study adds to this literature by showing that in women, incident clinical vertebral fractures may have a similar impact on the progression of frailty as incident hip fractures. Vertebral fractures were previously found to increase the risk of death [22], and to substantially affect individual’s quality of life [23]. Therefore, an early detection and treatment of vertebral fractures may be crucial for older women who are at a greater baseline risk of developing severe frailty than older men [24, 25].

Negative effects of obesity on frailty were suggested in other studies that showed a correlation between BMI and frailty, and increases in risks of fractures and falls in obese individuals [19, 26‐28]. A relationship between obesity and frailty is complex and best explained through the phenomenon of sarcopenic obesity that represents a disproportional increase in fat mass as compared to the amount of muscle mass [21, 29‐31]. This imbalance amplifies with aging, leading to poor muscle strength, poor muscle quality, and increased disability [4, 29, 31]. However, our study suggests that physical activity decelerates frailty even after controlling for the negative effects of fractures and obesity, which is in agreement with the findings of several systematic reviews suggesting a reduction of frailty with exercise interventions [4].

Frailty is a multidimensional concept including both psychosocial impairments and a physical function decline; consequently, a holistic approach for treating frailty has been suggested [7]. Our study findings support this recommendation: although the strongest predictors of frailty progression were related to physical frailty, factors related to a psychosocial construct such as HRQL, cognitive functioning, and living arrangement also represented important contributors. Current research has been mainly focused on examining causes, pharmacological and non-pharmacological treatments for sarcopenia [32, 33]. Future studies should examine if culturally tailored psychosocial interventions improve older adults’ well-being and their compliance to interventions aimed to decelerate physical frailty.

Our study has some limitations. CaMos is a population-based community dwelling study that did not include institutionalized seniors or those with cognitive impairments who are potentially the frailest of all. Also, non-linear changes in CFI, observed in some cohorts, indicate that although variability in a degree of frailty exists among individuals, any increase is conditioned on the starting state and any decline signifies survivor effects. Non-participation, survivor or attrition bias in epidemiologic studies of older people represents a common threat for the generalisability of study findings [34]. Despite this, our conclusions remained robust in sensitivity analyses.

We showed that older adults with incident clinical vertebral fractures, hip fractures or obesity are at risk for more rapid progression of frailty. These individuals represent high-risk groups that should be considered for tailored frailty interventions. Future research should examine how nutrition, exercise and non-smoking interventions aimed at promoting healthy lifestyle for reducing frailty can be combined with psycho-social supports so that a short-term decrease in frailty progression transforms into a long-term reversal resulting in overall improvements of adults’ well-being and the optimal process of aging.