Impact of Different Sarcopenia Stages on the Postoperative New Osteoporotic Vertebral Compression Fracture After Percutaneous Kyphoplasty

Purpose The purpose of this study was to evaluate the impact of different sarcopenia stages on osteoporotic vertebral compression refracture (OVCRF) and identify other risk factors of new osteoporotic vertebral compression fracture (OVCF). We conducted a large, retrospective study of patients who underwent percutaneous kyphoplasty (PKP) for OVCF. Sarcopenia was staged as “presarcopenia”, “sarcopenia”, and “severe sarcopenia” according to the denition of the European Working Group on Sarcopenia in Older People. Univariate and multivariate analyses evaluating the risk factors for OVCRF were performed. and severe sarcopenia were independent risk factors for OVCRF, as well as low BMD, advanced age and female.


Introduction
Along with the increase of aging population, the elderly osteoporotic vertebral compression fracture (OVCF) incidence also showed a trend of increased gradually. OVCF is a common clinical condition which is characterized by back pain, with limited mobility. Conservative treatment such as bed rest, symptomatic treatment by oral analgesic drugs, will lead to long-term bed complications. For patients with obvious symptoms, percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP) has become a ne treatment due to its advantages of less trauma, rapid analgesia, and support for early outof-bed activity in elderly patients [1,2]. However, with the wide application of this technique, postoperative new vertebral fracture has become a common complication [3,4], causing secondary pain to patients and seriously affecting patients' treatment con dence and functional recovery. Therefore, it is important to identify those risk factor for OVCF recurrence and take appropriate interventions.
Sarcopenia is an age-related syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength, associated with functional impairment and disability [5]. Although recent studies have demonstrated that sarcopenia is closely related to osteoporosis [6], the association of sarcopenia and vertebral compression fractures has been rarely investigated. The European Working Group on Sarcopenia (EWGSOP1) has previously classi ed this condition graded as "presarcopenia", "sarcopenia", and "severe sarcopenia" according to severity [7]. It is assumed that the negative impact of sarcopenia on the clinical outcomes would be more severe with advancing sarcopenia stages. In this study, we applied the EWGSOP2 sarcopenia classi cation in patients who underwent PKP for OVCF. We aimed to investigate the impact of different sarcopenia stages on osteoporotic vertebral compression refracture and identify other risk factors of refractures.

Methods
From January 2017 to December 2018, consecutive patients who underwent percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fracture (OVCF) at the Spine Surgical Department of our hospital were included in this retrospective study. The inclusion criteria were as follows: (1) rst-ever acute or subacute single-level vertebral compression fracture planned to treated with PKP; (2) underwent preoperative plain lm radiography, computed tomography (CT), and magnetic resonance imaging; (3) agreed to take part in the study and signed the informed consent. The exclusion criteria included: (1) previous spinal surgery; (2) pathological fracture, including fractures related to malignancy, infection, or other medical conditions; (3) burst fracture with retro-pulsed bony fragment into the spinal canal and accompanied by neurologic signs before surgery; (4) had complication after surgery, including leakage of cement into the spinal canal, or postoperative neurologic de cit; (5) patients concomitant with severe physical disease who could not adhere to the follow-up visits (had American Society of Anesthesiologists grade≧ ); (6) use of steroids; (7) residual back pain(VAS ≧ 4 at 1 month after surgery); and (8) refracture of cemented vertebra. All the patients were prescribed 1-alpha-OH Vitamin D3 (0.5 mcg /day), an active Vitamin D supplement and encouraged to take the medication during 1 year follow-up. The patients were routinely followed up monthly in the outpatient department for the rst 3 months after the operation and subsequently at 3-month intervals with regular radiologic studies and osteoporotic medications, or at any point when there was recurrent back pain. New symptomatic fractures was de ned as a recurrent back pain and con rmed by MRI. If the patients was lost to follow-up, they would be excluded from our study.

Data collection
For each patient enrolled in this study, the following data were collected: (1) the patient demographic and clinical features, including age, sex, body mass index(BMI), hemoglobin concentration (hemoglobin concentration < 120 g/L for men and < 110 g/L for women was de ned as anemia), serum albumin concentration (serum albumin < 35 g/L was de ned as hypoproteinemia), comorbidity, diabetes, American Society of Anesthesiologists (ASA) grade, nutritional risk screening 2002 (NRS 2002) scores, lumber bone mineral density(BMD); (2) vertebral fracture image characters, including the fracture level, cement leakage into the disk, vacuum clefts, fracture severity grade. Fracture level of T5-T10, T11-L2, and L3-L5 were de ned as thoracic, thoracolumbar, and lumbar segments, respectively. Bone cement intervertebral leakage were veri ed by intraoperative and postoperative X-ray. Vacuum clefts were identi ed with pre-procedural plain radiography, CT and MR imaging. Fracture severity grade was characterized as mild (20%-25% collapse), moderate (26%-40% collapse), or severe (> 40% collapse) according to the semiquantitative classi cation of Genant et al [8]. Besides, the percentage of vertebral body height collapse less than 20% was de ned as "very mild".
De nition of different sarcopenia stages: The European Working Group on Sarcopenia (EWGSOP1) has recommended that sarcopenia be strati ed as "presarcopenia," "sarcopenia," and "severe sarcopenia," based on the severity of this condition [7]. Thus, we classi ed different sarcopenia stages according to three factor (muscle strength, muscle mass, physical performance) of the updated algorithm proposed by European Working Group on Sarcopenia (EWGSOP2) [9]. "Presarcopenia" is characterized by low muscle strength without the reduction of muscle mass or physical performance; "sarcopenia" is characterized by low muscle strength, plus low muscle mass, "severe sarcopenia" is characterized by low muscle strength, plus low muscle mass and low physical performance; and patients who did not have any of these de ciencies were classi ed as "normal".
Measurement of muscle strength, muscle mass and physical performance.
A whole body scan for body composition examination was measured with dual energy X-ray absorptiometry (DXA), and appendicular skeletal muscle mass (kg) were recorded. For the EWGSOP2's defnition, low muscle mass (LMM) was defned as having appendicular skeletal muscle mass less than 7 kg/m 2 in men and 6 kg/m 2 in women, respectively [10].
As recommended by the Asian Working Group for Sarcopenia (AWGS), handgrip strength and 6-meter usual gait speed were used for the measurement of muscle strength and physical performance, respectively [11]. Grip strength was measured on the dominant hand using an electronic hand dynamometer (EH101; Camry, Guangdong Province, China). Low handgrip strength was de ned as ≤ 26 kg for men and ≤ 18 kg for women; low gait speed was de ned as ≤ 0.8 m/s [12]. For the measurement of the 6-m usual gait speed, patients were asked to walk over a 6-m course at their usual speed. Patients were encouraged to mobilize early after PKP, mainly by walking out of bed. These two tests were conducted postoperatively both 1 day and 1 month, and the best value of 3 consecutive tests was recorded. We used the data of 1 month after surgery, and patients with residual back pain (VAS ≧ 4 at 1 month after surgery) was excluded to avoid interfering with measurement, although no new vertebral fractures have been con rmed by MRI in these patients.

Statistical analysis.
The results are expressed as mean ± SD. The Kolmogorov-Smirnov test was used to determine the normality of continuous data. Statistical signi cance was evaluated using Student's t-test or one-way ANOVA for continuous normally distributed data. For continuous, non-normally distributed data, the Mann-Whitney U test and Kruskal-Wallis tests were used. Categorical data were compared using the Chisquared test or Fisher exact test. P<0.05 was considered statistically signi cant.
To evaluate the risk factors for subsequent fractures, all variables associated with vertebral refractures with P < 0.1 from the univariate analyses were entered into multivariate forward COX regression analysis. Furthermore, Kaplan-Meier analysis was used to determine the cumulative recurrence-free rates according to different sarcopenia stages. All statistical analyses were performed with SPSS for Windows, version 21.0(SPSS Inc., Chicago, IL, USA).

Results
A total of 511 consecutively admitted patients with acute or subacute single-level vertebral compression fracture were screened, and 329 met the entry criteria (Fig. 1). Patient characteristics are summarized in Table 1, the mean age of all the patients was 71.26 years, and the majority of patients (n = 274, 83.3%) were female.  The one-way ANOVA was used to assess normally distributed variables, the Kruskal-Wallis test was used for non-normally distributed variables. The chi-square test or Fisher's Exact test was used for categorical variables.
Based on the diagnostic criteria, 67 (20.4%), 43 (13.1%), and 24 (7.3%) of patients were identi ed as having "presarcopenia", "sarcopenia", and "severe sarcopenia", respectively, whereas 195 (59.3%) of patients were identi ed as "normal". As is shown in Table 1, the handgrip strength, appendicular skeletal muscle mass index, gait speed signi cantly lower with advancing sarcopenia stages. Gender, ASA grade, diabetes, and hemoglobin, treated vertebral level did not differ signi cantly between different sarcopenia stages. Patients with sarcopenia and severe sarcopenia were older, and had lower BMI, lower preoperative serum albumin compared with normal patients, but patients with presarcopenia did not. Patients with presarcopenia, sarcopenia and severe sarcopenia had lower BMD than normal patients.  The time to recurrence event was analyzed by Kaplane-Meier survival curves based on stages of sarcopenia. Patients with sarcopenia and severe sarcopenia had a higher risk of recurrence event compared to patients with presarcopenia and normal patients, P < 0.001; Fig. 2).

Discussion
We enrolled a large sample size to identify the OVCF patients with different stages of sarcopenia according to EWGSOP sarcopenia classi cation by assessing muscle strength, muscle mass and physical performance. The cut-off values of handgrip strength and 6-meter usual gait speed were according to AWGS because of the eastern people generally have a smaller physique and a lower BMI than the western people. To avoid the effects of pain and movement restriction, handgrip strength and 6meter usual gait speed were measured post-operation.
The relationship between sarcopenia and vertebral compression fractures has been preliminarily explored. Iolascon et al. [13] con rmed that the rate of sarcopenia increasing along with the number of vertebral fragility fractures in women. A cross-sectional study examined 216 women with fresh OVCF, the result showed sarcopenia were independent risk factors for acute OVCF [14]. However, both two studies de nition of sarcopenia only included skeletal muscle mass as the unique parameter. Thus, the sarcopenic patients identi ed by these studies could have presarcopenia, sarcopenia, or severe sarcopenia. One study in community-dwelling elderly subjects showed that elderly subjects with sarcopenia had a greater risk of falls compared with normal elderly subjects, but those with presarcopenia did not [15]. Another study in women with a hip fracture showed that sarcopenic women had a lower ability to function in their activities of daily living than presarcopenic women [16]. These results demonstrated the value of sarcopenia classi cation for a better risk strati cation. A total of 72 (21.9%) recurrent OVCF occurred during our 1-year follow-up and the refracture rate was increased in advancing sarcopenia patients (20.9% vs 32.6% vs 54.2%, respectively). Our multivariate analysis also demonstrated that sarcopenia, severe sarcopenia were independent risk factors for OVCRF, whereas presarcopenia was not.
The reasons why OVCF recurrence rate increased in advanced sarcopenia stage remain uncertain, the following reasons can be hypothesized. First, a large proportion of fragility fractures in patients with osteoporosis are reported to be caused by falls [17]. Muscle mass and strength as critical components in maintaining physical function, mobility, and vitality [18]. Low muscle quality would lead to physical disability and frailty, and subsequently increase the risk of falls. Previous studies have reported patients with sarcopenia over 80 -year -old were approximate three times to have a fall than non-sarcopenia patients within two years [19]. Second, advanced sarcopenia stage was associated with a lower BMD in the present study (Table 1,P = 0.007). Two large sample data study con rmed sarcopenia was associated with osteopenia and osteoporosis in Asian area [20,21]. For patients with low BMD, the quality of the vertebral bodies was poor, resulting in a greater probability of OVCRF. Bone and muscle are not only adjacent to each other in anatomy, but also indispensable in basic metabolism. Recently, it has become clear that bone and muscle share genetic determinants [22]. The close interaction between bone loss and muscle wasting results in the co-occurrence of osteoporosis and sarcopenia, named osteosarcopenia [23]. Furthermore, some researchers have found a synergistic effect between osteoporosis and sarcopenia, lead to the occur of fragility fracture [24].
Low bone mineral density is another risk factor for recurrent fractures in this study. odds ratio in the multivariate model. We therefore concluded that sarcopenia, severe sarcopenia had much stronger prediction power for the occurrence of postoperative OVCRF than BMD.
Advanced sarcopenia stage was associated with lower BMI (P = 0.000), lower serum albumin level (P = 0.008) and higher NRS 2002 scores (P = 0.000) in the present study(  [26]. However, none of the traditional nutritional indices, such as BMI, albumin levels and NRS 2002 scores, were associated with OVCRF. We speculated that sarcopenia is a more comprehensive parameter than these traditional nutritional indices, re ecting not only the nutritional status but also the functional status. Moreover, skeletal muscle mass has been reported to be a new index for nutritional assessment [27]. Existing research has focused more on anti-osteoporosis treatment to prevent recurrence of fractures [28,29], the present study indicated that anti-sarcopenia could be regarded as a potential therapeutic target in the future. We think resistance training program such as knee extension/ exion and leg presses to offset sarcopenia could be carried out at the appropriate time after surgery. Adequate nutritional intake and certain nutritional supplements, such as leucine and omega-3 polyunsaturated fatty acids, could have a synergistic effect with resistance training in maintaining muscle mass [30]. Age and sex were statistically signi cant difference between the OVCRFs group and non-OVCRFs group in univariate analysis. Other risk factors like treated vertebral level, vacuum clefts, intradiscal cement leakage, and AP ratio showed no difference between the two groups, which were still controversial [25,31,32]. Meanwhile, multivariate analysis revealed that female (OR 6.325; 95% CI 2.176-18.368, p = 0.001) and older age (OR 1.863; 95% CI 1.002-3.464, p = 0.049) were related to OVCRFs after PKP in our study. As people getting older, the quantity and mass of trabeculae will decrease simultaneously. The absorption of calcium in the digestive system decreases at the same time, leading to the loss of bone mass in elderly patients, especially postmenopausal women [33,34]. Lidsay et al. [35] observed that almost 20% of women would experience another fracture within 1 year of an incident vertebral fracture.
The present study was strengthened by its large sample retrospective study design, the strict inclusion and exclusion criteria, and rigorous follow-up strategy. Our department is one of the largest spine centers in China, performing > 400 OVCF operations annually, which enabled the study to be nished within a short time range. However, there are still several limitations. First, this is a single-center study, the conclusions of this study need to be validated in multicenter studies in the future. Second, only symptomatic subsequent fractures were included. The actual subsequent fractures rate would be higher than the observed rate. Third, there were differences in the use of anti-osteoporosis drugs during postoperative follow-up, which may resulted in a biased refracture rate.

Conclusion
In conclusion, symptomatic subsequent fractures occurred in 21.8% of the patients with rst-time and single-level fractures during the year following PKP treatment. This study demonstrated that patients had higher OVCRF rate with advancing sarcopenia stages. Sarcopenia and severe sarcopenia were identi ed as independent risk factor for OVCRF, whereas presarcopenia was not.
Low BMD T-scores, advanced age and female are other risk factors for OVCRF. Our work emphasized the value of recognizing sarcopenia stages, in terms of performing a better risk strati cation, as well as helping to set an appropriate strategy to avoid recurring fractures.

Availability of data and materials
Datasets are available from the corresponding author on reasonable request.
Ethics approval and consent to participate The study protocol was approved by the Medical Ethics Committee of the First A liated Hospital of Wenzhou Medical University. Written informed consents were obtained from patients or their relatives.

Consent for publication
Consent for publication was obtained from the patients or their relatives.
Competing interests