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Sarcopenia is more prevalent in men than in women after hip fracture: A cross-sectional study of 591 inpatients
Archives of Gerontology and Geriatrics 55 (2012) e48–e52
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Sarcopenia is more prevalent in men than in women after hip fracture: A cross-sectional study of 591 inpatients Marco Di Monaco a,*, Carlotta Castiglioni a, Fulvia Vallero a, Roberto Di Monaco b, Rosa Tappero a a b
Osteoporosis Research Center, Division of Physical Medicine and Rehabilitation, Presidio Sanitario San Camillo, Strada Santa Margherita 136, 10131 Torino, Italy Department of Social Sciences, University, Via S. Ottavio 50, 10124 Torino, Italy
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 February 2012 Received in revised form 30 April 2012 Accepted 3 May 2012 Available online 28 May 2012
Our aim was to compare the prevalence of sarcopenia in men and women with hip fracture. We studied 591 of 630 hip fracture inpatients consecutively admitted to our Rehabilitation ward. All the patients underwent a Dual-Energy X-Ray Absorptiometry (DXA) scan 18.4 8.7 (mean SD) days after hip fracture occurrence. Sarcopenia was defined when appendicular lean mass divided by height squared was less than two standard deviations below the mean of the young reference group obtained from population based studies. Using normative data from the New Mexico Elder Health Study, 340 of the 531 women (64.0%), and 57 of the 60 men (95.0%) had sarcopenia. Using normative data from the survey performed in Rochester, Minnesota, 116 of the 531 women (21.8%), and 52 of the 60 men (86.7%) had sarcopenia. After adjustment for age, time between fracture occurrence and DXA scan, number of medications in use, and number of concomitant diseases, men had a significantly higher prevalence of sarcopenia than women (p < 0.001). The adjusted odds ratio was either 10.54 (95% CI from 3.25 to 34.16) or 23.64 (from 10.8 to 51.6) depending on the reference population adopted. Our data shows a high proportion of sarcopenic subjects after hip-fracture. Sarcopenia was significantly more prevalent in men than in women. Relevancy of prevention and treatment of muscle loss is emphasized, particularly in men. ß 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Dual-Energy X-Ray Absorptiometry (DXA) Frail elderly Hip fractures Sarcopenia
1. Introduction A decrease in muscle mass accompanies aging, as stated by several longitudinal studies (Fantin et al., 2007; Visser et al., 2003). Muscle loss is associated with mobility disorders, increased risk of falls, reduced ability to function in activities of daily living, loss of independence, and reduced life expectancy (Baumgartner et al., 1998; Bunout, De la Maza, Barrera, Leiva, & Hirsch, 2011; Janssen, 2006; Melton et al., 2000). Sarcopenia is the term used to define a geriatric syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability and death (Cruz-Jentoft et al., 2010; Lang et al., 2010). Hip-fracture patients are frail (Di Monaco, 2011; Hershkovitz, Polatov, Beloosesky, & Brill, 2010; Pioli, Davoli, Pellicciotti, Pignedoli, & Ferrari, 2011) and have a high risk of both death and disability: after hip fracture there is a 8–36% excess mortality within 1 year (Abrahamsen, van Staa, Ariely, Olson, & Cooper,
* Corresponding author. Tel.: +39 011 819 9411; fax: +39 011 819 3012. E-mail addresses: [email protected], [email protected] (M. Di Monaco). 0167-4943/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.archger.2012.05.002
2009) and approximately 20% of hip fracture survivors require long-term nursing home care, whereas only 40% fully regain their pre-injury level of independence (Clinician’s Guide, 2008). Sarcopenia is thought to play a role in the genesis of hip fracture, because it enhances the risk of falling (Cruz-Jentoft et al., 2010; Lang et al., 2010) and nearly all hip fractures occur as a result of a fall in individuals with reduced bone strength (Clinician’s Guide, 2008). Furthermore, the loss of muscle tissue seems strictly linked with the loss of bone mass and strength (Cruz-Jentoft et al., 2010; Lang et al., 2010; Polidoulis, Beyene, & Cheung, 2012). Overall, a sarcopenic individual is expected to be at high risk of both falls and bone fragility, i.e., the two conditions associated with an increased risk of hip fracture. Recently, a high prevalence of sarcopenia and a significant association between sarcopenia and osteoporosis have actually been shown in one sample of women with a fragility fracture of the hip (Di Monaco, Vallero, Di Monaco, & Tappero, 2011). The loss of muscle mass and strength is age-related in both men and women, although sex-specific characteristics of the aging process in muscle tissue have been observed (Doherty, 2001). Our aim was to compare the proportion of sarcopenic men and women after hip fracture. We hypothesized that sarcopenia prevalence may be different between sexes in hip fracture subjects.
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2. Subjects and methods 2.1. Patients and setting The study was performed in a city with about one-million inhabitants. We evaluated 630 white inpatients consecutively admitted to our physical medicine and rehabilitation division because of their first hip fracture. We focused on white patients because few non-white elderly subjects live in our country. The patients came from several orthopedic wards from various hospitals and were referred for acute inpatient rehabilitation by the consultant physiatrists of the orthopedic wards who referred for inpatient rehabilitation about 70% of the hip fracture survivors. Twenty-five of the 630 patients we evaluated were excluded from our study because their hip fractures resulted from either major trauma or cancer affecting bone. The remaining 605 patients sustained fractures that either were spontaneous or resulted from minimal trauma (trauma equal to or less than a fall from a standing position). Four of these patients were excluded from our study because they had hip or knee arthroplasties that could alter DualEnergy X-Ray Absorptiometry (DXA) assessment. The remaining 601 subjects were asked to undergo a DXA scan. Ten of these 601 subjects refused to undergo DXA assessment and were excluded from the study. The final study sample included 591 patients (531 women and 60 men) who gave their informed consent to undergo DXA assessment. The patients were recruited during a 40-month period. A sample size of 580 subjects was calculated hypothesizing a sarcopenia prevalence in women = 73% (Di Monaco, Vallero, et al., 2011) and an allocation ratio of 8.5, to detect a 15% difference in sarcopenia prevalence between women and men (power 80%; alpha 0.05). Institution Revision Board approval was obtained for the study protocol. 2.2. Outcome measures DXA (QDR 4500W, Hologic, Inc.) was used to measure whole and regional body composition. Appendicular lean mass (aLM) was calculated as the sum of lean mass (LM) in arms and legs. Because metal implants (prostheses, plates, screws, and nails) were reported to affect the regional assessment of body composition with overestimation of LM (Giangregorio & Webber, 2003) and to avoid the confounding role of postoperative edema, we performed a preliminary comparison between LM assessed at fractured legs and at contralateral legs. At a paired T-test, LM assessed at fractured legs in the 531 women (5299.2 1091.7 g; mean SD) was significantly higher than LM assessed at unfractured legs (4840.4 986.2 g); the mean between-side difference was 458.8 g (95% CI 400.7–517.0; p < 0.001). Similarly, in the 60 men LM assessed at fractured legs (6597.9 1365.7) was significantly higher than LM assessed at unfractured legs (6172.3 1242.1); the mean between-side difference was 425.6 g (95% CI 245.6–605.6; p < 0.001). To avoid LM overestimation at fractured legs, we
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corrected aLM by substituting LM in unfractured leg for LM in fractured leg: corrected aLM = (LM in unfractured leg 2) + LM in arms, as previously described (Di Monaco, Castiglioni, Vallero, Di Monaco, & Tappero, 2011; Di Monaco, Vallero, et al., 2011). LM cannot be interpreted without some indexing to body size: it is necessary to account for height when comparisons are performed among different subjects. Height was assessed by a standard method (with the patients standing) in the majority of the patients, whereas twenty subjects, who could not keep the standing position, were measured supine. We accounted for body size by dividing corrected aLM by height squared (aLM/ht2). Sarcopenia was defined when aLM was less than two standard deviations below the mean of the young reference group (Baumgartner et al., 1998; Melton et al., 2000). Normative data for aLM were derived from either the New Mexico Elder Health Study (Baumgartner et al., 1998) or the survey performed by Melton LJ et al. in Rochester, Minnesota (Melton et al., 2000). Thresholds for aLM/ht2 to define sarcopenia in women were 5.45 kg/m2 and 4.51 kg/m2, respectively for the two reference populations. Thresholds in men were 7.26 kg/m2 and 6.77 kg/m2, respectively. In each patient we recorded age, number of medications in use, number of concomitant diseases, and time interval between fracture occurrence and DXA scan as potential confounders. 2.3. Statistical analyses Preliminary comparisons between men and women were performed by an unpaired T-test. The association between sarcopenia and sex was investigated by a chi-square test for independence. A binary logistic regression test was used to adjust the association between sex and sarcopenia (dependent variable) for age, number of medications in use, number of concomitant diseases, and interval between fracture occurrence and DXA scan. The statistical package used was SPSS, version 14. 3. Results Descriptive statistics for the 591 patients are shown in Table 1. Using normative data from the New Mexico Elder Health Study, 340 of the 531 women (i.e., 64%), and 57 of the 60 men (i.e., 95%) had sarcopenia. The association between sex and sarcopenia was significant: x2(1, n = 591) = 22.1, p < 0.001. Significance was maintained after adjustment for age, number of medications in use, number of concomitant diseases and time between fracture occurrence and DXA scan, as shown in Table 2. Using normative data from the survey performed in Rochester, Minnesota, 116 of the 531 women (i.e., 21.8%), and 52 of the 60 men (i.e., 86.7%) had sarcopenia. The association between sex and sarcopenia was significant: x2(1, n = 591) = 108.2, p < 0.001. Significance was maintained after adjustments, as shown in Table 3.
Table 1 Descriptives in the 531 women and 60 men (given as mean and standard deviation).
Age, years Height, cm Weight, kg Medications in use (number) Concomitant diseases (number) Corrected appendicular lean mass, g Corrected appendicular lean mass/height2, g/m2 Interval fracture occurrence – DXA scan, days
Women
Men
p
80.0 (7.4) 157.1 (6.3) 56.3 (11.6) 3.6 (1.5) 2.7 (0.8) 12,787 (2343) 5175.7 (879.5) 18.3 (8.8)
81.4 (7.5) 169.9 (9.1) 65.4 (12.7) 3.4 (1.3) 2.8 (0.6) 16,812 (3143) 5807.5 (871.9) 19.4 (8.2)
0.16 <0.001 <0.001 0.39 0.85 <0.001 <0.001 0.34
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Table 2 Binary logistic regression analysis: factors associated with the presence of sarcopenia defined according to the normative data from the New Mexico Elder Health Study. B (standard error) Sex Age (years) Interval fracture – DXA scan (days) Number of medications Number of concomitant diseases
2.35 (0.6) 0.01 (0.01) 0.004 (0.01) 0.02 (0.06) 0.13 (0.12)
Wald
Odds ratio and 95% CI
p
15.41 1.16 0.11 0.07 1.18
10.54 (3.25–34.16) 1.01 (0.99–1.04) 1.00 (0.98–1.02) 1.02 (0.90–1.15) 0.88 (0.69–1.11)
<0.001 0.27 0.74 0.78 0.28
The dependent variable was the presence of sarcopenia (that was conventionally attributed a value of 1, whereas the absence of sarcopenia was conventionally attributed a value of 0). The independent variables included in the regression model are listed in the table. Male sex was conventionally attributed a value of 1 (female sex was attributed a value of 0).
Table 3 Binary logistic regression analysis: factors associated with the presence of sarcopenia defined according to the normative data from the survey performed in Rochester, Minnesota. B (standard error) Sex Age (years) Interval fracture – DXA scan (days) Number of medications Number of concomitant diseases
3.16 0.03 0.03 0.02 0.25
(0.40) (0.01) (0.01) (0.07) (0.14)
Wald
Odds ratio and 95% CI
p
62.95 5.52 6.05 0.06 3.03
23.64 (10.8–51.6) 1.03 (1.01–1.06) 1.03 (1.01–1.05) 1.02 (0.88–1.18) 0.78 (0.58–1.03)
<0.001 0.019 0.014 0.802 0.082
The dependent variable was the presence of sarcopenia (that was conventionally attributed a value of 1, whereas the absence of sarcopenia was conventionally attributed a value of 0). The independent variables included in the regression model are listed in the table. Male sex was conventionally attributed a value of 1 (female sex was attributed a value of 0).
4. Discussion A substantial proportion of the hip-fracture women included in this study had sarcopenia, as recently shown (Di Monaco, Vallero, et al., 2011). Nevertheless, men had a significantly higher prevalence of sarcopenia than women. The adjusted odds ratio was either 10.54 or 23.64 depending on the reference population adopted for sarcopenia definition. To our knowledge no previous studies compared sarcopenia prevalence in men and women following a fracture of the hip. Data suggests that an accelerated loss of muscle mass may play a role in hip-fracture genesis in both sexes, with a more relevant role in men than in women, although caution is needed in interpreting our results because the crosssectional design of the study does not prove causal inference. We emphasize the relevancy of interventions aimed at preventing sarcopenia in the community. Physical exercise effectively counteracts age related muscle loss improving both strength and performance even in frail subjects, with modest requirements of time (sessions of 30 min twice per week of resistive exercise) and equipment (Lang et al., 2010; Waters, Baumgartner, Garry, & Vellas, 2010). Other interventions that may favorably affect the muscle include diet changes (increase in protein intakes and administration of vitamin D supplements) and hormonal therapies (including sex steroids, growth hormone, and insulin-like growth factor-I), although hormones have a questionable risk-benefit ratio (Boirie, 2009; Lang et al., 2010; Waters et al., 2010). Novel pharmacologic approaches, including selective androgen receptor modulators and myostatin inhibitors, are under study (Lang et al., 2010; Waters et al., 2010). The view that the loss of DXA-assessed aLM may have a different relevancy depending on sex is consistent with four previous studies on the functional recovery following hip fracture. The level of aLM assessed after a fracture of the hip did not affect ability to function in activities of daily living and functional performance in women (Di Monaco, Vallero, Di Monaco, Tappero, & Cavanna, 2006; Visser et al., 2000; Wehren, Hawkes, Hebel, Orwig, & Magaziner, 2005), whereas it significantly predicted the functional outcome in men (Di Monaco, Vallero, Di Monaco, Tappero, & Cavanna, 2007). The relevancy of hip fractures in men
has been underestimated, because osteoporosis is more common among women (Clinician’s Guide, 2008). However, one of three to five of the overall number of hip fractures occur in men (Johnell & Kanis, 2006), and they carry a higher risk of death, complications, and institutionalization than hip fractures occurring in women (Abrahamsen et al., 2009; Kannegaard, van der Mark, Eiken, & Abrahamsen, 2010; Morin et al., 2011, 2012). Very recently, male sex has been associated with a worse recovery of ability to function in activities of daily living in a large sample of hip fracture subjects following acute inpatient rehabilitation, independently of comorbidity (Di Monaco, Castiglioni, Vallero, Di Monaco, & Tappero, 2012). The role of a more pronounced muscle loss may contribute to explain the functional disadvantage found in hip fracture men. In future rehabilitation protocols a more aggressive intervention to restore muscle strength in men should be tested. Reference data for sarcopenia are not universally agreed upon. We used normative data from each of the two large populationbased studies that investigated DXA-assessed aLM (Baumgartner et al., 1998; Melton et al., 2000). According to the authors, sarcopenia was diagnosed when aLM/ht2 was less than two standard deviations below the mean of the young reference group. Notably, despite changes in sarcopenia prevalence due to the change of the reference population, for both normative data we found a significant difference in the proportion of sarcopenic subjects between sexes, with a higher proportion in men than in women. We did not investigate the mechanisms underlying the association between sex and sarcopenia. One possible explanation rests on the well-known higher prevalence of chronic comorbidity preceding the fracture in men. Because hip-fracture men are in worse general health conditions than women (Abrahamsen et al., 2009), the higher proportion of sarcopenic men may simply be due to the higher proportion of comorbid, frail men. Similarly, higher comorbidity has been thought to cause the increased risk of death found in men. However, the higher mortality among male hipfracture patients compared to women was found even when controlling for number of medications and chronic comorbidity (Kannegaard et al., 2010; Morin et al., 2011). Similarly, in our study adjustments for number of concomitant diseases and number of
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medications in use did not affect the significant between-sex difference in the prevalence of sarcopenia. Alternatively, the difference in the prevalence of sarcopenia between sexes after hip fracture may mirror the difference found in the general population, given a trend toward an accelerated loss of LM in older men described in population-based studies (Baumgartner et al., 1998; Li, Ford, Zhao, Balluz, & Giles, 2009; Melton et al., 2000). However, the difference between sexes we show in hip-fracture patients seems much higher than the one found in population-based studies. Finally, a sex-associated pattern of aging in the muscle tissue has been hypothesized (Doherty, 2001), given the importance of hormonal factors, including sex steroids, growth hormone and insulin-like growth factor-I, in affecting muscle mass and quality (Boirie, 2009; LeBlanc et al., 2011; Pollanen et al., 2011; Waters, Yau, Montoya, & Baumgartner, 2003). Differences in the aging process of the muscle may underlie a stronger association between muscle loss and hip fracture in men than in women. Indeed, sex-related differences in muscle aging were shown, although a precise definition of the sex-related mechanisms involved both at the whole muscle and single fiber levels need further investigation (Krivickas et al., 2006). Aging is a known major determinant of muscle loss. In our study, age was significantly associated with sarcopenia defined according to normative data from the survey study performed in Rochester, but not from the Mexico Elder Health study. The limited age range of our sample may have contributed to this inconsistent result. Our study has limitations. We evaluated white patients admitted to a single rehabilitation hospital in Italy, who agreed to be studied and who could be evaluated by DXA. As a consequence, data cannot be generalized to the overall population of hip-fracture patients. We assessed aLM by DXA. This method has a good reported reproducibility and was validated against multislice computed tomography scans, magnetic resonance imaging, and body composition models (Albanese, Diessel, & Genant, 2003). However, DXA does not capture qualitative changes of the muscle that occur with aging and may impair muscle performance irrespectively of muscle mass. Unfortunately, we did not collect data on muscle strength and physical performance. However, strength and performance assessed after the fracture are not easily interpretable, because they are affected by several confounders, including pain, falls and fear of falling, comorbidities, complications, nutritional status, medications, cognitive impairment, delirium, postoperative mobilization, and depression (Kristensen, 2011). We performed DXA assessment after hip fracture. The interval between fracture occurrence and DXA assessment may be a confounding variable in our study, because relevant changes in body composition, including a decrease in LM, have been shown after hip fracture. In a prospective study, the percentage of decrease in LM was 6.4% two months after fracture occurrence (Fox et al., 2000). In our study the loss of LM is expected to be lower, because we performed DXA assessment about 18 days after fracture occurrence. A shorter time (i.e., a few days) between fracture occurrence and DXA assessment may be better to minimize the changes in aLM, but many patients cannot undergo DXA scan a few days after fracture occurrence. Anyway, no differences in time between fracture occurrence and DXA scan were found between men and women. Furthermore, to adjust our results for this potential confounder, we included it in binary logistic regression analysis as an independent variable. 5. Conclusions Data shows a high proportion of sarcopenic subjects after hipfracture, with a significantly higher prevalence in men than in women. We emphasize a research approach on preventive
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strategies and treatment options for sarcopenia and osteoporosis targeting both bone and muscle tissue (Adunsky et al., 2011; Boirie, 2009; Di Monaco, Vallero, Di Monaco, Tappero, & Cavanna, 2009; Lang et al., 2010; Waters et al., 2010). This may be the case for lifestyle changes (i.e., increase in physical activity and optimal protein nutrition) and medications that exert anabolic actions, although type and dosage of each intervention should be specifically investigated. The higher prevalence of sarcopenia in men may lead to sex-specific rehabilitation protocols following a fracture of the hip (Di Monaco et al., 2007). Finally, our results should be taken into account when the costs associated with sarcopenia are estimated. At now, sarcopenia is thought to impose a relevant economic burden on healthcare services because it enhances the risk of physical disability in elderly subjects (Janssen, Shepard, Katzmarzyk, & Roubenoff, 2004). 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Sarcopenia is more prevalent in men than in women after hip fracture: A cross-sectional study of 591 inpatients Marco Di Monaco a,*, Carlotta Castiglioni a, Fulvia Vallero a, Roberto Di Monaco b, Rosa Tappero a a b
Osteoporosis Research Center, Division of Physical Medicine and Rehabilitation, Presidio Sanitario San Camillo, Strada Santa Margherita 136, 10131 Torino, Italy Department of Social Sciences, University, Via S. Ottavio 50, 10124 Torino, Italy
A R T I C L E I N F O
A B S T R A C T
Article history: Received 27 February 2012 Received in revised form 30 April 2012 Accepted 3 May 2012 Available online 28 May 2012
Our aim was to compare the prevalence of sarcopenia in men and women with hip fracture. We studied 591 of 630 hip fracture inpatients consecutively admitted to our Rehabilitation ward. All the patients underwent a Dual-Energy X-Ray Absorptiometry (DXA) scan 18.4 8.7 (mean SD) days after hip fracture occurrence. Sarcopenia was defined when appendicular lean mass divided by height squared was less than two standard deviations below the mean of the young reference group obtained from population based studies. Using normative data from the New Mexico Elder Health Study, 340 of the 531 women (64.0%), and 57 of the 60 men (95.0%) had sarcopenia. Using normative data from the survey performed in Rochester, Minnesota, 116 of the 531 women (21.8%), and 52 of the 60 men (86.7%) had sarcopenia. After adjustment for age, time between fracture occurrence and DXA scan, number of medications in use, and number of concomitant diseases, men had a significantly higher prevalence of sarcopenia than women (p < 0.001). The adjusted odds ratio was either 10.54 (95% CI from 3.25 to 34.16) or 23.64 (from 10.8 to 51.6) depending on the reference population adopted. Our data shows a high proportion of sarcopenic subjects after hip-fracture. Sarcopenia was significantly more prevalent in men than in women. Relevancy of prevention and treatment of muscle loss is emphasized, particularly in men. ß 2012 Elsevier Ireland Ltd. All rights reserved.
Keywords: Dual-Energy X-Ray Absorptiometry (DXA) Frail elderly Hip fractures Sarcopenia
1. Introduction A decrease in muscle mass accompanies aging, as stated by several longitudinal studies (Fantin et al., 2007; Visser et al., 2003). Muscle loss is associated with mobility disorders, increased risk of falls, reduced ability to function in activities of daily living, loss of independence, and reduced life expectancy (Baumgartner et al., 1998; Bunout, De la Maza, Barrera, Leiva, & Hirsch, 2011; Janssen, 2006; Melton et al., 2000). Sarcopenia is the term used to define a geriatric syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as physical disability and death (Cruz-Jentoft et al., 2010; Lang et al., 2010). Hip-fracture patients are frail (Di Monaco, 2011; Hershkovitz, Polatov, Beloosesky, & Brill, 2010; Pioli, Davoli, Pellicciotti, Pignedoli, & Ferrari, 2011) and have a high risk of both death and disability: after hip fracture there is a 8–36% excess mortality within 1 year (Abrahamsen, van Staa, Ariely, Olson, & Cooper,
* Corresponding author. Tel.: +39 011 819 9411; fax: +39 011 819 3012. E-mail addresses: [email protected], [email protected] (M. Di Monaco). 0167-4943/$ – see front matter ß 2012 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.archger.2012.05.002
2009) and approximately 20% of hip fracture survivors require long-term nursing home care, whereas only 40% fully regain their pre-injury level of independence (Clinician’s Guide, 2008). Sarcopenia is thought to play a role in the genesis of hip fracture, because it enhances the risk of falling (Cruz-Jentoft et al., 2010; Lang et al., 2010) and nearly all hip fractures occur as a result of a fall in individuals with reduced bone strength (Clinician’s Guide, 2008). Furthermore, the loss of muscle tissue seems strictly linked with the loss of bone mass and strength (Cruz-Jentoft et al., 2010; Lang et al., 2010; Polidoulis, Beyene, & Cheung, 2012). Overall, a sarcopenic individual is expected to be at high risk of both falls and bone fragility, i.e., the two conditions associated with an increased risk of hip fracture. Recently, a high prevalence of sarcopenia and a significant association between sarcopenia and osteoporosis have actually been shown in one sample of women with a fragility fracture of the hip (Di Monaco, Vallero, Di Monaco, & Tappero, 2011). The loss of muscle mass and strength is age-related in both men and women, although sex-specific characteristics of the aging process in muscle tissue have been observed (Doherty, 2001). Our aim was to compare the proportion of sarcopenic men and women after hip fracture. We hypothesized that sarcopenia prevalence may be different between sexes in hip fracture subjects.
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2. Subjects and methods 2.1. Patients and setting The study was performed in a city with about one-million inhabitants. We evaluated 630 white inpatients consecutively admitted to our physical medicine and rehabilitation division because of their first hip fracture. We focused on white patients because few non-white elderly subjects live in our country. The patients came from several orthopedic wards from various hospitals and were referred for acute inpatient rehabilitation by the consultant physiatrists of the orthopedic wards who referred for inpatient rehabilitation about 70% of the hip fracture survivors. Twenty-five of the 630 patients we evaluated were excluded from our study because their hip fractures resulted from either major trauma or cancer affecting bone. The remaining 605 patients sustained fractures that either were spontaneous or resulted from minimal trauma (trauma equal to or less than a fall from a standing position). Four of these patients were excluded from our study because they had hip or knee arthroplasties that could alter DualEnergy X-Ray Absorptiometry (DXA) assessment. The remaining 601 subjects were asked to undergo a DXA scan. Ten of these 601 subjects refused to undergo DXA assessment and were excluded from the study. The final study sample included 591 patients (531 women and 60 men) who gave their informed consent to undergo DXA assessment. The patients were recruited during a 40-month period. A sample size of 580 subjects was calculated hypothesizing a sarcopenia prevalence in women = 73% (Di Monaco, Vallero, et al., 2011) and an allocation ratio of 8.5, to detect a 15% difference in sarcopenia prevalence between women and men (power 80%; alpha 0.05). Institution Revision Board approval was obtained for the study protocol. 2.2. Outcome measures DXA (QDR 4500W, Hologic, Inc.) was used to measure whole and regional body composition. Appendicular lean mass (aLM) was calculated as the sum of lean mass (LM) in arms and legs. Because metal implants (prostheses, plates, screws, and nails) were reported to affect the regional assessment of body composition with overestimation of LM (Giangregorio & Webber, 2003) and to avoid the confounding role of postoperative edema, we performed a preliminary comparison between LM assessed at fractured legs and at contralateral legs. At a paired T-test, LM assessed at fractured legs in the 531 women (5299.2 1091.7 g; mean SD) was significantly higher than LM assessed at unfractured legs (4840.4 986.2 g); the mean between-side difference was 458.8 g (95% CI 400.7–517.0; p < 0.001). Similarly, in the 60 men LM assessed at fractured legs (6597.9 1365.7) was significantly higher than LM assessed at unfractured legs (6172.3 1242.1); the mean between-side difference was 425.6 g (95% CI 245.6–605.6; p < 0.001). To avoid LM overestimation at fractured legs, we
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corrected aLM by substituting LM in unfractured leg for LM in fractured leg: corrected aLM = (LM in unfractured leg 2) + LM in arms, as previously described (Di Monaco, Castiglioni, Vallero, Di Monaco, & Tappero, 2011; Di Monaco, Vallero, et al., 2011). LM cannot be interpreted without some indexing to body size: it is necessary to account for height when comparisons are performed among different subjects. Height was assessed by a standard method (with the patients standing) in the majority of the patients, whereas twenty subjects, who could not keep the standing position, were measured supine. We accounted for body size by dividing corrected aLM by height squared (aLM/ht2). Sarcopenia was defined when aLM was less than two standard deviations below the mean of the young reference group (Baumgartner et al., 1998; Melton et al., 2000). Normative data for aLM were derived from either the New Mexico Elder Health Study (Baumgartner et al., 1998) or the survey performed by Melton LJ et al. in Rochester, Minnesota (Melton et al., 2000). Thresholds for aLM/ht2 to define sarcopenia in women were 5.45 kg/m2 and 4.51 kg/m2, respectively for the two reference populations. Thresholds in men were 7.26 kg/m2 and 6.77 kg/m2, respectively. In each patient we recorded age, number of medications in use, number of concomitant diseases, and time interval between fracture occurrence and DXA scan as potential confounders. 2.3. Statistical analyses Preliminary comparisons between men and women were performed by an unpaired T-test. The association between sarcopenia and sex was investigated by a chi-square test for independence. A binary logistic regression test was used to adjust the association between sex and sarcopenia (dependent variable) for age, number of medications in use, number of concomitant diseases, and interval between fracture occurrence and DXA scan. The statistical package used was SPSS, version 14. 3. Results Descriptive statistics for the 591 patients are shown in Table 1. Using normative data from the New Mexico Elder Health Study, 340 of the 531 women (i.e., 64%), and 57 of the 60 men (i.e., 95%) had sarcopenia. The association between sex and sarcopenia was significant: x2(1, n = 591) = 22.1, p < 0.001. Significance was maintained after adjustment for age, number of medications in use, number of concomitant diseases and time between fracture occurrence and DXA scan, as shown in Table 2. Using normative data from the survey performed in Rochester, Minnesota, 116 of the 531 women (i.e., 21.8%), and 52 of the 60 men (i.e., 86.7%) had sarcopenia. The association between sex and sarcopenia was significant: x2(1, n = 591) = 108.2, p < 0.001. Significance was maintained after adjustments, as shown in Table 3.
Table 1 Descriptives in the 531 women and 60 men (given as mean and standard deviation).
Age, years Height, cm Weight, kg Medications in use (number) Concomitant diseases (number) Corrected appendicular lean mass, g Corrected appendicular lean mass/height2, g/m2 Interval fracture occurrence – DXA scan, days
Women
Men
p
80.0 (7.4) 157.1 (6.3) 56.3 (11.6) 3.6 (1.5) 2.7 (0.8) 12,787 (2343) 5175.7 (879.5) 18.3 (8.8)
81.4 (7.5) 169.9 (9.1) 65.4 (12.7) 3.4 (1.3) 2.8 (0.6) 16,812 (3143) 5807.5 (871.9) 19.4 (8.2)
0.16 <0.001 <0.001 0.39 0.85 <0.001 <0.001 0.34
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Table 2 Binary logistic regression analysis: factors associated with the presence of sarcopenia defined according to the normative data from the New Mexico Elder Health Study. B (standard error) Sex Age (years) Interval fracture – DXA scan (days) Number of medications Number of concomitant diseases
2.35 (0.6) 0.01 (0.01) 0.004 (0.01) 0.02 (0.06) 0.13 (0.12)
Wald
Odds ratio and 95% CI
p
15.41 1.16 0.11 0.07 1.18
10.54 (3.25–34.16) 1.01 (0.99–1.04) 1.00 (0.98–1.02) 1.02 (0.90–1.15) 0.88 (0.69–1.11)
<0.001 0.27 0.74 0.78 0.28
The dependent variable was the presence of sarcopenia (that was conventionally attributed a value of 1, whereas the absence of sarcopenia was conventionally attributed a value of 0). The independent variables included in the regression model are listed in the table. Male sex was conventionally attributed a value of 1 (female sex was attributed a value of 0).
Table 3 Binary logistic regression analysis: factors associated with the presence of sarcopenia defined according to the normative data from the survey performed in Rochester, Minnesota. B (standard error) Sex Age (years) Interval fracture – DXA scan (days) Number of medications Number of concomitant diseases
3.16 0.03 0.03 0.02 0.25
(0.40) (0.01) (0.01) (0.07) (0.14)
Wald
Odds ratio and 95% CI
p
62.95 5.52 6.05 0.06 3.03
23.64 (10.8–51.6) 1.03 (1.01–1.06) 1.03 (1.01–1.05) 1.02 (0.88–1.18) 0.78 (0.58–1.03)
<0.001 0.019 0.014 0.802 0.082
The dependent variable was the presence of sarcopenia (that was conventionally attributed a value of 1, whereas the absence of sarcopenia was conventionally attributed a value of 0). The independent variables included in the regression model are listed in the table. Male sex was conventionally attributed a value of 1 (female sex was attributed a value of 0).
4. Discussion A substantial proportion of the hip-fracture women included in this study had sarcopenia, as recently shown (Di Monaco, Vallero, et al., 2011). Nevertheless, men had a significantly higher prevalence of sarcopenia than women. The adjusted odds ratio was either 10.54 or 23.64 depending on the reference population adopted for sarcopenia definition. To our knowledge no previous studies compared sarcopenia prevalence in men and women following a fracture of the hip. Data suggests that an accelerated loss of muscle mass may play a role in hip-fracture genesis in both sexes, with a more relevant role in men than in women, although caution is needed in interpreting our results because the crosssectional design of the study does not prove causal inference. We emphasize the relevancy of interventions aimed at preventing sarcopenia in the community. Physical exercise effectively counteracts age related muscle loss improving both strength and performance even in frail subjects, with modest requirements of time (sessions of 30 min twice per week of resistive exercise) and equipment (Lang et al., 2010; Waters, Baumgartner, Garry, & Vellas, 2010). Other interventions that may favorably affect the muscle include diet changes (increase in protein intakes and administration of vitamin D supplements) and hormonal therapies (including sex steroids, growth hormone, and insulin-like growth factor-I), although hormones have a questionable risk-benefit ratio (Boirie, 2009; Lang et al., 2010; Waters et al., 2010). Novel pharmacologic approaches, including selective androgen receptor modulators and myostatin inhibitors, are under study (Lang et al., 2010; Waters et al., 2010). The view that the loss of DXA-assessed aLM may have a different relevancy depending on sex is consistent with four previous studies on the functional recovery following hip fracture. The level of aLM assessed after a fracture of the hip did not affect ability to function in activities of daily living and functional performance in women (Di Monaco, Vallero, Di Monaco, Tappero, & Cavanna, 2006; Visser et al., 2000; Wehren, Hawkes, Hebel, Orwig, & Magaziner, 2005), whereas it significantly predicted the functional outcome in men (Di Monaco, Vallero, Di Monaco, Tappero, & Cavanna, 2007). The relevancy of hip fractures in men
has been underestimated, because osteoporosis is more common among women (Clinician’s Guide, 2008). However, one of three to five of the overall number of hip fractures occur in men (Johnell & Kanis, 2006), and they carry a higher risk of death, complications, and institutionalization than hip fractures occurring in women (Abrahamsen et al., 2009; Kannegaard, van der Mark, Eiken, & Abrahamsen, 2010; Morin et al., 2011, 2012). Very recently, male sex has been associated with a worse recovery of ability to function in activities of daily living in a large sample of hip fracture subjects following acute inpatient rehabilitation, independently of comorbidity (Di Monaco, Castiglioni, Vallero, Di Monaco, & Tappero, 2012). The role of a more pronounced muscle loss may contribute to explain the functional disadvantage found in hip fracture men. In future rehabilitation protocols a more aggressive intervention to restore muscle strength in men should be tested. Reference data for sarcopenia are not universally agreed upon. We used normative data from each of the two large populationbased studies that investigated DXA-assessed aLM (Baumgartner et al., 1998; Melton et al., 2000). According to the authors, sarcopenia was diagnosed when aLM/ht2 was less than two standard deviations below the mean of the young reference group. Notably, despite changes in sarcopenia prevalence due to the change of the reference population, for both normative data we found a significant difference in the proportion of sarcopenic subjects between sexes, with a higher proportion in men than in women. We did not investigate the mechanisms underlying the association between sex and sarcopenia. One possible explanation rests on the well-known higher prevalence of chronic comorbidity preceding the fracture in men. Because hip-fracture men are in worse general health conditions than women (Abrahamsen et al., 2009), the higher proportion of sarcopenic men may simply be due to the higher proportion of comorbid, frail men. Similarly, higher comorbidity has been thought to cause the increased risk of death found in men. However, the higher mortality among male hipfracture patients compared to women was found even when controlling for number of medications and chronic comorbidity (Kannegaard et al., 2010; Morin et al., 2011). Similarly, in our study adjustments for number of concomitant diseases and number of
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medications in use did not affect the significant between-sex difference in the prevalence of sarcopenia. Alternatively, the difference in the prevalence of sarcopenia between sexes after hip fracture may mirror the difference found in the general population, given a trend toward an accelerated loss of LM in older men described in population-based studies (Baumgartner et al., 1998; Li, Ford, Zhao, Balluz, & Giles, 2009; Melton et al., 2000). However, the difference between sexes we show in hip-fracture patients seems much higher than the one found in population-based studies. Finally, a sex-associated pattern of aging in the muscle tissue has been hypothesized (Doherty, 2001), given the importance of hormonal factors, including sex steroids, growth hormone and insulin-like growth factor-I, in affecting muscle mass and quality (Boirie, 2009; LeBlanc et al., 2011; Pollanen et al., 2011; Waters, Yau, Montoya, & Baumgartner, 2003). Differences in the aging process of the muscle may underlie a stronger association between muscle loss and hip fracture in men than in women. Indeed, sex-related differences in muscle aging were shown, although a precise definition of the sex-related mechanisms involved both at the whole muscle and single fiber levels need further investigation (Krivickas et al., 2006). Aging is a known major determinant of muscle loss. In our study, age was significantly associated with sarcopenia defined according to normative data from the survey study performed in Rochester, but not from the Mexico Elder Health study. The limited age range of our sample may have contributed to this inconsistent result. Our study has limitations. We evaluated white patients admitted to a single rehabilitation hospital in Italy, who agreed to be studied and who could be evaluated by DXA. As a consequence, data cannot be generalized to the overall population of hip-fracture patients. We assessed aLM by DXA. This method has a good reported reproducibility and was validated against multislice computed tomography scans, magnetic resonance imaging, and body composition models (Albanese, Diessel, & Genant, 2003). However, DXA does not capture qualitative changes of the muscle that occur with aging and may impair muscle performance irrespectively of muscle mass. Unfortunately, we did not collect data on muscle strength and physical performance. However, strength and performance assessed after the fracture are not easily interpretable, because they are affected by several confounders, including pain, falls and fear of falling, comorbidities, complications, nutritional status, medications, cognitive impairment, delirium, postoperative mobilization, and depression (Kristensen, 2011). We performed DXA assessment after hip fracture. The interval between fracture occurrence and DXA assessment may be a confounding variable in our study, because relevant changes in body composition, including a decrease in LM, have been shown after hip fracture. In a prospective study, the percentage of decrease in LM was 6.4% two months after fracture occurrence (Fox et al., 2000). In our study the loss of LM is expected to be lower, because we performed DXA assessment about 18 days after fracture occurrence. A shorter time (i.e., a few days) between fracture occurrence and DXA assessment may be better to minimize the changes in aLM, but many patients cannot undergo DXA scan a few days after fracture occurrence. Anyway, no differences in time between fracture occurrence and DXA scan were found between men and women. Furthermore, to adjust our results for this potential confounder, we included it in binary logistic regression analysis as an independent variable. 5. Conclusions Data shows a high proportion of sarcopenic subjects after hipfracture, with a significantly higher prevalence in men than in women. We emphasize a research approach on preventive
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strategies and treatment options for sarcopenia and osteoporosis targeting both bone and muscle tissue (Adunsky et al., 2011; Boirie, 2009; Di Monaco, Vallero, Di Monaco, Tappero, & Cavanna, 2009; Lang et al., 2010; Waters et al., 2010). This may be the case for lifestyle changes (i.e., increase in physical activity and optimal protein nutrition) and medications that exert anabolic actions, although type and dosage of each intervention should be specifically investigated. The higher prevalence of sarcopenia in men may lead to sex-specific rehabilitation protocols following a fracture of the hip (Di Monaco et al., 2007). Finally, our results should be taken into account when the costs associated with sarcopenia are estimated. At now, sarcopenia is thought to impose a relevant economic burden on healthcare services because it enhances the risk of physical disability in elderly subjects (Janssen, Shepard, Katzmarzyk, & Roubenoff, 2004). 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