LOW LEVELS OF 25-hydroxyvitamin D were significantly

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1 271 ORIGINAL ARTICLE Appendicular Lean Mass Does Not Mediate the Significant Association Between Vitamin D Status and Functional Outcome in Hip-Fracture Women Marco Di Monaco, MD, Carlotta Castiglioni, MD, Fulvia Vallero, MD, Roberto Di Monaco, PhD, Rosa Tappero, MD ABSTRACT. Di Monaco M, Castiglioni C, Vallero F, Di Monaco R, Tappero R. Appendicular lean mass does not mediate the significant association between vitamin D status and functional outcome in hip-fracture women. Arch Phys Med Rehabil 2011;92: Objective: To investigate whether muscle mass mediates the significant association between vitamin D status and functional recovery after hip fracture in women. Design: Observational study. Setting: Rehabilitation hospital in Italy. Participants: We investigated white women (N 280) of 305 who were consecutively admitted to a rehabilitation hospital because of their first fracture of the hip. Interventions: Not applicable. Main Outcome Measures: To assess muscle mass, we measured appendicular lean mass (alm) by dual-energy x-ray absorptiometry (DXA), (mean SD) days after hip fracture occurrence in the 280 women. On the same day, we assessed serum levels of 25-hydroxyvitamin D and parathyroid hormone (PTH). Ability to function in activities of daily living was evaluated by the Barthel Index both before and after acute inpatient rehabilitation. Results: After adjustment for 8 confounders, including age, cognitive impairment, pressure ulcers, neurologic impairment, infections, fracture type, Barthel Index score at admission to rehabilitation, and alm/height 2 (alm/ht 2 ), 25-hydroxyvitamin D levels were significantly associated both with Barthel Index scores after rehabilitation (P.003) and their changes during rehabilitation (P.008). Similar results were obtained when the 25-hydroxyvitamin D/PTH ratio was substituted for 25- hydroxyvitamin D levels. Conversely, alm/ht 2 was not significantly correlated with Barthel Index scores and their changes during rehabilitation. Furthermore, we found no significant associations between either 25-hydroxyvitamin D levels or the 25-hydroxyvitamin D/PTH ratio and alm/ht 2. Conclusions: The significant association between 25-hydroxyvitamin D levels (and 25-hydroxyvitamin D/PTH ratio) and the ability to function in women with hip fractures was not mediated by alm assessed by DXA. Key Words: Activities of daily living; Hip fractures; Parathyroid hormone; Rehabilitation; Vitamin D by the American Congress of Rehabilitation Medicine LOW LEVELS OF 25-hydroxyvitamin D were significantly associated with the occurrence of hip fractures in prospective studies. 1-3 Three recent meta-analyses showed the effectiveness of vitamin D supplements for hip fracture prevention, either when doses of more than 400IU/d of the vitamin were administered alone 4 or when a combination of calcium and vitamin D was supplied, 5,6 although controversies still exist on fracture reduction as a result of vitamin-d supplementation in community dwellers. 7 The administration of both calcium and vitamin D is recommended worldwide to reduce the risk of fracture, 8,9 but substantial proportions of older people are still affected by vitamin D deficiency, 10,11 and very low serum levels of 25-hydroxyvitamin D are common among disabled people 12,13 and at the time of hospitalization for a fracture of the hip Survivors of hip fracture are at high risk of permanent disability. Up to 25% of them may require long-term nursing home care, and only 40% fully regain their prefracture level of independence. 8 Notably, vitamin D deficiency was shown to affect independence in activities of daily living, lower extremity function, and risk of falling after hip fracture, 14,15 apart from influencing the risk of fracture. Secondary hyperparathyroidism resulting from vitamin D deficiency was suggested to contribute to generate postfracture disability. 17 One possible explanation of the effects exerted by vitamin D deficiency and PTH excess on functional recovery after a fracture of the hip rests on the reduction of MM. A loss of MM was associated with disability in the elderly, and people with hip fractures are commonly affected by sarcopenia (ie, the clinical condition of having abnormally low levels of MM). 23 Skeletal muscles require vitamin D for structural maintenance and optimal function, with deficiency causing loss of MM, an atrophy of type II muscle fibers, and muscle weakness We hypothesized that vitamin D and PTH status may affect the ability of women with hip fractures to function by altering their MM levels. To assess this hypothesis we studied the From the Osteoporosis Research Center (M. Di Monaco, Castiglioni, Vallero) and the Division of Physical Medicine and Rehabilitation (Tappero), Presidio Sanitario San Camillo; and Department of Social Science, University (R. Di Monaco), Torino, Italy. Supported in part by Regione Piemonte, Ricerca Sanitaria Finalizzata. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Correspondence to Marco Di Monaco, MD, Osteoporosis Research Center, Presidio Sanitario San Camillo, Strada Santa Margherita , Torino, Italy, Medici@h-sancamillo.to.it; marco.di.monaco@alice.it /11/ $36.00/0 doi: /j.apmr alm alm/ht 2 BMI DXA LM MM PTH List of Abbreviations appendicular lean mass alm divided by height squared body mass index dual-energy x-ray absorptiometry lean mass muscle mass parathyroid hormone

2 272 HIP FRACTURE, VITAMIN D, AND LEAN MASS, Di Monaco relationship between vitamin D status, PTH levels, MM, and functional recovery in one sample of older women with a recent hip fracture. METHODS Participants We evaluated 305 white women consecutively admitted to our physical medicine and rehabilitation division during a 22-month period because of their first hip fracture. The mean SD value of time between fracture occurrence and admission to the rehabilitation hospital was days. We focused on white women because few nonwhite elderly women live in Italy. Twenty-five women were excluded from the study: 14 had hip fractures from either major trauma or cancer affecting bone, 4 had hip or knee arthroplasties that could alter the assessment of body composition, and 7 could not undergo body composition assessment because of refusal, death, or acute diseases. The final study sample included 280 women who gave their informed consent to participate in the study. Of these 280 women, 102 were also included in a recently published cross-sectional study on the prevalence of sarcopenia and its association with osteoporosis in women with a hip fracture. 23 All the fractures were either spontaneous or caused by minimal trauma (trauma equal to or less than a fall from the standing position). The study protocol was approved by the regional committee for scientific research (Regione Piemonte). Outcome Measures We used DXA (QDR 4500W a ) to measure whole and regional body composition. We followed the protocol for DXA total body scan as described by the manufacturer. alm was calculated as the sum of LM in arms and legs. Because metal implants (prostheses and nails) were reported to affect the regional assessment of body composition with overestimation of LM, 28,29 we performed a preliminary comparison between LM assessed at fractured legs and at contralateral legs. At paired t test, LM assessed at fractured legs ( g; mean SD) was significantly higher than LM assessed at unfractured legs ( g) in the 280 women (difference between sides, 503g; 95% confidence interval, g; P.001). To avoid LM overestimation at fractured legs, we corrected alm by substituting LM in the unfractured leg for LM in the fractured leg: corrected alm (LM in unfractured leg 2) LM in arms, as previously described. 23,29 LM cannot be interpreted without some indexing to body size. At a minimum, 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 8 women who could not keep the standing position were measured supine. We accounted for body size by dividing corrected alm by height squared (alm/ht 2 ), as previously reported in 2 epidemiologic studies 30,31 focusing on the prevalence of sarcopenia. These 2 studies 30,31 supplied normative data for alm/ht 2. A blood sample was collected on the day of DXA scan, (mean SD) days after fracture occurrence, while patients were fasting. In each woman, we evaluated 25-hydroxyvitamin D levels by an immunoenzymatic assay b (coefficient of variation intra-assay, 8%; interassay, 10%), and intact PTH by 2-site chemiluminescent enzyme-labeled immunometric assay c (coefficient of variation intra-assay, 5.7%; interassay, 8.8%). Normal values for 25-hydroxyvitamin D were above 30ng/mL; vitamin D deficiency was diagnosed when 25-hydroxyvitamin D levels were below 12ng/mL, whereas values between 12 and 30ng/mL defined vitamin D insufficiency. Hyperparathyroidism was diagnosed when PTH levels exceeded 80pg/mL. We did not record information on vitamin D supplementation and treatment with medications for osteoporosis before fracture occurrence. None of the women received medications for osteoporosis, vitamin D, or calcium supplementation during the time interval between fracture occurrence and 25-hydroxyvitamin D assessment. Functional evaluation, both at rehabilitation admission and at discharge from the rehabilitation hospital, was assessed by skilled physiatrists with the use of the Barthel Index (original version unchanged). The functional index assesses basic activities of daily living; its score ranges from 0 (total dependence) to 100 (total independence). The physiatrists were not aware of the results of both body composition and laboratory assessments at the time of Barthel Index score evaluation. Data Analysis We investigated bivariate linear correlations between the potential predictors (ie, 25-hydroxyvitamin D, PTH, 25-hydroxyvitamin D/PTH ratio, and alm/ht 2 ), Barthel Index scores assessed after rehabilitation, and their changes during rehabilitation by using a Spearman rank test. Furthermore, we took into account the role of 11 potential confounders: age, BMI, hip fracture type (cervical or trochanteric), surgical procedure type (arthroplasty or internal fixation), cognitive impairment (Mini-Mental State Examination score, 24/30), pressure ulcers (stage 2 or higher according to the classification from the National Pressure Ulcer Advisory Panel), neurologic impairment (impairment found at clinical examination caused by neurologic diseases, ie, Parkinson disease, stroke with hemiplegia, paraparesis, monoparesis, tetraparesis, or cerebellar syndrome), infections (all the infections needing antibiotic treatment during the length of stay), comorbidities (all the prevalent diseases judged clinically relevant during the length of stay), number of medications in use, and Barthel Index score at admission to inpatient rehabilitation. Descriptive statistics for the 280 women are shown in table 1. We had no missing data. BMI was evaluated both as individual values and after categorization in 4 classes, in agreement Table 1: Characteristics of the 280 Women Included in the Study Age (y) BMI (kg/m 2 ) Hip fracture type: trochanteric/cervical 57/43 Surgical procedure type: arthroplasty/ internal fixation 55/45 Cognitive impairment 21 Pressure ulcers 28 Neurologic impairment 14 Infections 51 No. of concomitant diseases No. of medications in use Barthel Index score at admission to inpatient rehabilitation 45 (35 55) Barthel Index score at discharge from inpatient rehabilitation 90 (75 95) 25-Hydroxyvitamin D (ng/ml) 8.9 ( ) PTH (pg/ml) 46 ( ) Corrected alm (g) 13, Corrected alm/ht 2 (g/m 2 ) NOTE. Values are mean SD, percentages, or median (interquartile range).

3 HIP FRACTURE, VITAMIN D, AND LEAN MASS, Di Monaco 273 Table 2: Multiple Regression Analysis Model Variables with the World Health Organization recommendations: 48 women were underweight (BMI, 18.5kg/m 2 ), 165 were normal ( kg/m 2 ), 49 were overweight ( kg/m 2 ), and 18 were obese ( 30kg/m 2 ). At a preliminary step, we assessed the relationship between each potential confounder and functional scores after rehabilitation and their changes during rehabilitation, by using a Spearman rank correlation test for both continuous and ordinal variables and a Mann-Whitney test for dichotomous variables. For 7 of the 11 potential confounders (ie, age, cognitive impairment, pressure ulcers, neurologic impairment, infections, fracture type, and Barthel Index score at admission to rehabilitation), we found at least one significant relationship either with functional scores after rehabilitation or with their changes during rehabilitation. We included these 7 potential confounders together with the 25-hydroxyvitamin D/PTH ratio and alm/ht 2 as independent variables in a linear multiple regression model. The dependent variable in the regression model was the Barthel Index score assessed at the end of inpatient rehabilitation. The same analysis was repeated after substituting the changes in the Barthel Index scores during rehabilitation for the Barthel Index scores assessed at the end of inpatient rehabilitation. Because the dependent variables (Barthel Index scores and their changes) were nonnormally distributed, area transformation was performed, using the formula (r 1/2)/w, where w is the number of observations and r is the rank. 15 After area transformation of the dependent variables, the residuals were normally distributed in the regression models. Homoscedasticity was verified by plotting the residuals against the predicted values; the variance of the residuals looked homogeneous across levels of the predicted values. Collinearity diagnostics showed that the percent of variance in each predictor that could not be accounted for by the other predictors was always greater than 78% (no redundant predictors were found). Multiple regression analyses were repeated after substituting either 25-hydroxyvitamin D or PTH levels for the 25-hydroxyvitamin D/PTH ratio. The statistical package used was SPSS, version 14. d RESULTS One hundred seventy-four of the 280 women had serum levels of 25-hydroxyvitamin D below 12ng/mL, 87 had levels Partial Correlation Barthel Index score at admission to rehabilitation Age Neurologic impairment Cognitive impairment Hydroxyvitamin D/PTH ratio Infections during the stay in hospital Fracture type Pressure ulcers alm/ht NOTE. The dependent variable was the Barthel Index score assessed at the end of acute inpatient rehabilitation (after normalization by area transformation). The independent variables were those listed in the table. Cognitive impairment, neurologic impairment, pressure ulcers, and infections during the stay in hospital were conventionally attributed a value of 1 (the absence of these conditions was conventionally attributed a value of 0). R 2.49; F 43.9; P.001. P between 12 and 30ng/mL, and 19 women had levels above 30ng/mL. Secondary hyperparathyroidism was found in 59 of the 280 women. At a Spearman rank test, we showed a significant correlation between both 25-hydroxyvitamin D and PTH levels assessed before rehabilitation and Barthel Index scores assessed at discharge from rehabilitation; values were.157 (P.009) and.206 (P.001), respectively. Also, the ratio between 25-hydroxyvitamin D and PTH levels was significantly correlated with the Barthel Index scores (.232; P.001). Conversely, we did not find any significant correlations between alm/ht 2 assessed before rehabilitation and Barthel Index scores assessed after rehabilitation (.004; P.94), 25-hydroxyvitamin D (.025; P.682), PTH (.069; P.248), and 25-hydroxyvitamin D/PTH ratio (.057; P.345). Results of the multiple regression model are shown in table 2. After adjustment for 8 variables including alm/ht 2, we found a significant positive association between the 25-hydroxyvitamin D/PTH ratio and Barthel Index scores assessed after rehabilitation (P.004). Results were similar when 25-hydroxyvitamin D (but not PTH) values were substituted for the 25-hydroxyvitamin D/PTH ratio ( value for the partial correlation between 25-hydroxyvitamin D and Barthel Index scores was.178, P.003; value for the partial correlation between PTH and Barthel Index scores was.88, P.146, data not shown in detail). The Barthel Index score increased in all the women during inpatient rehabilitation; the median increase was 40 (total range, 5 85; interquartile range, 30 45). At a Spearman rank test, 25-hydroxyvitamin D levels, PTH levels, 25-hydroxyvitamin D/PTH ratio, and alm/ht 2 assessed before rehabilitation were not significantly correlated with the change in the Barthel Index scores during inpatient rehabilitation ( values were.066,.024,.067, and.041, respectively). Results of multiple regression are shown in table 3. After adjustment for 8 variables including alm/ht 2, we found a significant association between the 25-hydroxyvitamin D/PTH ratio and the change in Barthel Index scores during inpatient rehabilitation (P.030). Results were similar when 25-hydroxyvitamin D (but not PTH) values were substituted for the 25-hydroxyvitamin D/PTH ratio ( value for the partial correlation between 25-hydroxtvitamin D and Barthel Index scores was.159, P.008; value for the partial correlation between PTH and Barthel Index scores was.061, P.311, data not shown in detail). Table 3: Multiple Regression Analysis Model Variables Partial Correlation Barthel Index score at admission to rehabilitation Neurologic impairment Age Cognitive impairment Hydroxyvitamin D/PTH ratio Infections during the stay in hospital Pressure ulcers alm/ht Fracture type NOTE. The dependent variable was the change in the Barthel Index score during acute inpatient rehabilitation (after normalization by area transformation). The independent variables were those listed in the table. Cognitive impairment, neurologic impairment, pressure ulcers, and infections during the stay in hospital were conventionally attributed a value of 1 (the absence of these conditions was conventionally attributed a value of 0). R 2.32; F 25.7; P.001. P

4 274 HIP FRACTURE, VITAMIN D, AND LEAN MASS, Di Monaco DISCUSSION Serum levels of 25-hydroxyvitamin D and the 25-hydroxyvitamin D/PTH ratio were significantly associated with the ability of women with a hip fracture to function after inpatient rehabilitation, in agreement with previous reports. 14,15,17 Conversely, alm/ht 2 was not significantly associated with ability to function. Furthermore, we found no significant associations between either 25-hydroxyvitamin D levels or the 25-hydroxyvitamin D/PTH ratio and alm/ht 2. Altogether, our data indicate that the significant association between vitamin D status and the ability to function in our sample of women with a hip fracture was not mediated by alm. In agreement with our current data, 4 previous studies of women with hip fractures showed no significant associations between alm assessed by DXA and measures of function, including mobility, 32 ability to perform activities of daily living, 29,33 and performance on lower extremity tasks. 34 Data Interpretation The lack of a significant association between vitamin D status and alm may depend on the limited range of both these variables in our sample. Indeed, vitamin D deficiency was highly prevalent, in agreement with previous studies of people with hip fractures, and few women (ie, 19 of 280) had normal levels of 25-hydroxyvitamin D. Absolute values of alm/ht 2 seemed low in our patients, although they are not easily interpretable, because of the incomplete definition of normative data. In fact, few attempts were made to investigate alm in population-based studies to establish normal values and sarcopenia prevalence. Baumgartner et al 31 studied 199 subjects in the New Mexico Health Study. With sarcopenia defined as alm/ht 2 greater than 2 SDs below the young normal mean, and the cutoff value calculated to be 5.45kg/m 2, 31% of the women 60 years and older fulfilled the diagnostic criterion of sarcopenia. Using the same criterion, Melton III et al 30 found a lower cutoff value (4.51kg/m 2 ) and a lower prevalence of sarcopenia (8%) among the women 60 years and older in the population-based study of 694 subjects performed in Rochester, Minnesota. We did not study a reference population of young subjects to establish normal values. Using the cutoff value pointed out by Baumgartner, we found that 154 (55%) of 280 of our patients had sarcopenia, whereas with the use of the cutoff value indicated by Melton III, the prevalence of sarcopenia was 18% (51/280). Besides the limitations of the normative data, the prevalence of sarcopenia in our patients seemed high, as expected, given older age and frailty. We cannot exclude significant relationships between 25-hydroxyvitamin D levels and alm in other samples of people with higher serum levels of the vitamin and higher levels of muscle mass. Notably, one previous longitudinal study showed that lower 25-hydroxyvitamin D and higher PTH levels increased the risk of sarcopenia. 25 It is possible that the cross-sectional design of our study and the limited range of the variables do not fully capture the relationship between 25-hydroxyvitamin D, PTH, and alm. Similarly, the lack of association between alm and function may depend on small differences among individual subjects that in turn limit the utility of alm assessment in this group of frail and older people. 34 An alternative explanation for the lack of significant associations between alm and function in women with a hip fracture rests on DXA failure in capturing qualitative changes of the muscle that impair its function. 29 Indeed, DXA is a validated technique for LM assessment, 35 but it does not capture qualitative alterations of the aging muscle, including fat infiltration, a decreased proportion of type II fibers, increased connective tissue, metabolic changes, and variations to the muscle spindle The changes in muscle quality and their confounding role may be greater in women than in men, 39 as suggested by the discrepancy between the 4 negative studies 29,32-34 in women and a single study 39 of men with hip fractures that showed a significant association between alm assessed by DXA and the ability to function in activities of daily living. Notably, 25-hydroxyvitamin D and PTH may act on the muscle at least partly through qualitative changes. This may explain the significant relationship between vitamin D status but not alm and functional ability in our sample. Vitamin D depletion induced negative changes in muscle contraction kinetics, and several steps essential for muscle contraction (ie, calcium uptake of sarcoplasmic reticulum, intracellular availability of both adenosine triphosphate and phosphate, and protein synthesis, including the synthesis of actin and troponin) were shown to be regulated by vitamin D In addition, vitamin D status was significantly associated with choice reaction time, a measurement reflecting neuroprotective mechanisms such as central processing, cognition, and motor response. 40,41 The effects of vitamin D on muscle tissue and the central nervous system may actually mediate the increased body sway and risk of falling, the impaired performance on lower extremity function tests, and the reduced ability to perform activities of daily living that were shown in vitamin D depleted subjects. Consistently, the administration of vitamin D affected muscle fiber composition and morphology in vitamin D deficient older adults 26 ; it improved muscle strength, functional performance of lower limbs, body sway, and the ability to function in activities of daily living 26,27,45-47 ; and it reduced the risk of falling, 48,49 although a definitive demonstration of vitamin D efficacy was not achieved in all settings Very high doses administered annually as a single dose may even increase the risk of falls and fractures. 53 It has been suggested that secondary hyperparathyroidism found in vitamin D depleted subjects may contribute to impaired muscle function. 17,25 Indeed, we found a significant association between PTH and functional outcome, but it was not confirmed after adjustment for several confounders. A potential role of PTH as an independent predictor of the functional outcome of women with a hip fracture needs further investigations. We showed that several factors were significantly associated with the functional outcome after acute inpatient rehabilitation in women with hip fractures, in agreement with previous reports. 54 The panel of prognostic factors we studied predicted 49% of the variance in the functional score and 32% of its change during rehabilitation. Study Limitations Our study has several limitations. Because our study has a cross-sectional design, data cannot prove causal inference. Metal implants (prostheses and nails) were reported to affect the regional assessment of body composition with overestimation of LM. 28,29 In agreement with these reports, our patients had a significantly higher LM at the fractured leg than at the contralateral leg. To avoid LM overestimation at fractured legs, we corrected alm by substituting LM in the unfractured leg for LM in the fractured leg, as previously described. 29 Our study included white women only. As a consequence, our data are not generalizable to the overall population of women who sustain hip fractures. The lack of a significant association between alm indexes and their potential determinants may depend on an inadequate statistical power; however, the number of women included in the study was proper to detect even a weak correlation (the study was powered at 80% to detect a significant correlation of r.17).

5 HIP FRACTURE, VITAMIN D, AND LEAN MASS, Di Monaco 275 It has been suggested that hip fracture itself with the accompanying restrictions on physical activity may change the relationship between alm and physical ability when alm is measured postoperatively. 55 In a prospective study, 56 the percentage of decrease in LM was 6.4% 2 months after fracture occurrence. In our study, the loss of LM is expected to be lower because we performed DXA assessment about 3 weeks after fracture occurrence. A shorter time (ie, a few days) may be better to minimize the changes in body composition, but many patients cannot undergo DXA assessment a few days after fracture occurrence. A relevant intermethod variability has been reported in the assessment of 25-hydroxyvitamin D, 57 and the immunoenzymatic assay we performed may overestimate the serum levels of the vitamin. 58 Seasonal variations may further affect the evaluation of vitamin D status. Finally, we did not investigate the role of potential confounders of interest, including protein intake and malnutrition. CONCLUSIONS We showed that the significant association between vitamin D and functional outcome after acute inpatient rehabilitation in women with a hip fracture is not mediated by alm. References 1. Cauley JA, LaCroix AZ, Wu L, et al. Serum 25 hydroxyvitamin D concentrations and the risk of hip fractures: the Women s Health Initiative. Ann Intern Med 2008;149: Looker AC, Mussolino ME. Serum 25-hydroxyvitamin D and hip fracture risk in older U.S. white adults. J Bone Miner Res 2008; 23: Cauley JA, Parimi N, Ensrud KE, et al, for the Osteoporotic Fractures in Men (MrOS) Research Group. Serum 25 hydroxyvitamin D and the risk of hip and non-spine fractures in older men. J Bone Miner Res 2010;25: Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med 2009;169: Avenell A, Gillespie WJ, Gillespie LD, O Connell D. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev 2009;15:CD DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68,500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 2010;340: Salovaara K, Tuppurainen M, Karkkainen M, et al. Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial the OSTPRE-FPS. J Bone Miner Res 2010;25: Physician s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation; Kanis JA, and the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2008;19: Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr 2008;87:1080S-6S. 11. Stechschulte SA, Kirsner RS, Federman DG. Vitamin D: bone and beyond, rationale and recommendations for supplementation. Am J Med 2009;122: Shinchuk LM, Morse L, Huancahuari N, Arum S, Chen TC, Holick MF. Vitamin D deficiency and osteoporosis in rehabilitation inpatients. Arch Phys Med Rehabil 2006;87: Smith EM, Comiskey CM, Carroll AM. A study of bone mineral density in adults with disability. Arch Phys Med Rehabil 2009; 90: LeBoff MS, Hawkes WG, Glowacki J, Yu-Yahiro J, Hurwitz S, Magaziner J. Vitamin D-deficiency and post-fracture changes in lower extremity function and falls in women with hip fractures. Osteoporos Int 2008;19: Di Monaco M, Vallero F, Di Monaco R, Mautino F, Cavanna A. Serum levels of 25-hydroxyvitamin D and functional recovery after hip fracture. Arch Phys Med Rehabil 2005;86: Gallacher SJ, McQuillian C, Harkness M, Finlay F, Gallacher AP, Dixon T. Prevalence of vitamin D inadequacy in Scottish adults with non-vertebral fragility fractures. Curr Med Res Opin 2005; 21: Di Monaco M, Vallero F, Di Monaco R, Tappero R, Cavanna A. 25-Hydroxyvitamin D, parathyroid hormone, and functional recovery after hip fracture in elderly patients. J Bone Miner Metab 2006;24: Newman AB, Kupelian V, Visser M, et al. Sarcopenia: alternative definitions and associations with lower extremity function. J Am Geriatr Soc 2003;51: Castillo EM, Goodman-Gruen D, Kritz-Silverstein D, Morton DJ, Wingard DL, Barrett-Connor E. Sarcopenia in elderly men and women: the Rancho Bernardo study. Am J Prev Med 2003;25: Janssen I. Influence of sarcopenia on the development of physical disability: the Cardiovascular Health Study. J Am Geriatr Soc 2006; Reid KF, Naumova EN, Carabello RJ, Phillips EM, Fielding RA. Lower extremity muscle mass predicts functional performance in mobility-limited elders. J Nutr Health Aging 2008;12: Fantin F, Di Francesco V, Fontana G, et al. Longitudinal body composition changes in old men and women: interrelationship with worsening disability. J Gerontol A Biol Sci Med Sci 2007; 62: Di Monaco M, Vallero F, Di Monaco R, Tappero R. Prevalence of sarcopenia and its association with osteoporosis in 313 older women following a fracture of the hip. Arch Gerontol Geriatr 2011;52: Pfeifer M, Begerow B, Minne HW. Vitamin D and muscle function. Osteoporos Int 2002;13: Visser M, Deeg DJ, Lips P. Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam. J Clin Endocrinol Metab 2003;88: Ceglia L. Vitamin D and skeletal muscle tissue and function. Mol Aspects Med 2008;29: Dam TT, von Muhlen D, Barrett-Connor EL. Sex-specific association of serum vitamin D levels with physical function in older adults. Osteoporos Int 2009;20: Giangregorio LM, Webber CE. Effects of metal implants on whole-body dual-energy x-ray absorptiometry measurements of bone mineral content and body composition. Can Assoc Radiol J 2003;54: Di Monaco M, Vallero F, Di Monaco R, Tappero R, Cavanna A. Muscle mass and functional recovery in women with hip fracture. Am J Phys Med Rehabil 2006;85: Melton LJ III, Khosla S, Crowson CS, O Connor MK, O Fallon WM, Riggs BL. Epidemiology of sarcopenia. J Am Geriatr Soc 2000;48: Baumgartner RN, Koeheler KM, Gallagher D, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol 1998;147: Visser M, Harris TB, Fox KM, et al. Change in muscle mass and muscle strength after a hip fracture: relationship to mobility recovery. J Gerontol A Biol Sci Med Sci 2000;55:M

6 276 HIP FRACTURE, VITAMIN D, AND LEAN MASS, Di Monaco 33. Wehren L, Hawkes W, Hebel JR, Orwig DL, Magaziner J. Bone mineral density, soft tissue body composition, strength, and functioning after hip fracture. J Gerontol A Biol Sci Med Sci 2005; 60: Miller RR, Shardell MD, Hicks GE, et al. Association of interleukin-6 with lower extremity function following hip fracture: the role of muscle mass and strength. J Am Geriatr Soc 2008;56: Albanese CV, Diessel E, Genant HK. Clinical applications of body composition measurements using DXA. J Clin Densitom 2003;6: Goodpaster BH, Carlson CL, Visser M, et al. Attenuation of skeletal muscle and strength in the elderly: the Health ABC study. J Appl Physiol 2001;90: Visser M, Kritchevsky SB, Goodpaster BH, et al. Leg muscle mass and composition in relation to lower extremity performance in men and women aged 70 to 79: the Health, Aging and Body Composition study. J Am Geriatr Soc 2002;50: Liu JX, Eriksson PO, Thornell LE, Pedrosa-Domellof F. Fiber content and myosin heavy chain composition of muscle spindles in aged human biceps brachii. J Histochem Cytochem 2005;53: Di Monaco M, Vallero F, Di Monaco R, Tappero R, Cavanna A. Muscle mass and functional recovery in hip-fracture men. Am J Phys Med Rehabil 2007;86: Dhesi JK, Jackson SH, Bearne LM, et al. Vitamin D supplementation improves neuromuscular function in older people who fall. Age Ageing 2004;33: Staud R. Vitamin D: more than just affecting calcium and bone. Curr Rheumatol Rep 2005;7: Bischoff HA, Stahelin HB, Urscheler N. Muscle strength in the elderly: its relation to vitamin D metabolites. Arch Phys Med Rehabil 1999;80: Isaia G, Giorgino R, Rini GB, Bevilacqua M, Maugeri D, Adami S. Prevalence of hypovitaminosis D in elderly women in Italy: clinical consequences and risk factors. Osteoporos Int 2003;14: Wicherts IS, van Schoor NM, Boeke AJ, et al. Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab 2007;92: Bischoff HA, Stahelin HB, Dick W, et al. Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial. J Bone Miner Res 2003;18: Pfeifer M, Begerow B, Minne HW, Suppan K, Fahrleitner- Pammer A, Dobnig H. Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int 2009;20: Lips P, Binkley N, Pfeifer M, et al. Once-weekly dose of 8400 IU vitamin D3 compared with placebo: effects on neuromuscular function and tolerability in older adults with vitamin D insufficiency. Am J Clin Nutr 2010;91: Dawson-Hughes B. Serum 25-hydroxyvitamin D and functional outcomes in the elderly. Am J Clin Nutr 2008;88:537S-40S. 49. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomized controlled trials. BMJ 2009;339: b Cameron ID, Murray GR, Gillespie LD, et al. Interventions for preventing falls in older people in nursing care facilities and hospitals. Cochrane Database Syst Rev 2010;CD Jackson C, Gaugris S, Sen SS, Hosking D. The effect of cholecalciferol (vitamin D3) on the risk of fall and fracture: a metaanalysis. QJM 2007;100: Gillespie LD, Robertson MC, Gillespie WJ, et al. Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev 2009;15:CD Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010;303: Di Monaco M. Functional outcome and hip-fracture type: moving beyond personal experience. Eur J Phys Rehabil Med 2008;44: Ogawa H, Oshita H, Ishimaru D, et al. Analysis of muscle atrophy after hip fracture in the elderly. Arch Phys Med Rehabil 2008;89: Fox KM, Magaziner J, Hawkes WG, et al. Loss of bone density and lean body mass after hip fracture. Osteoporos Int 2000;11: Roth HJ, Schmidt-Gayk H, Weber H, Niederau C. Accuracy and clinical implications of seven 25-hydroxyvitamin D methods compared with liquid chromatography-tandem mass spectrometry as a reference. Ann Clin Biochem 2008;45: Cavalier E, Huberty V, Cormier C, Souberbielle J. Overestimation of the 25OHD serum concentrations with the automated IDS EIA kit. J Bone Miner Res 2010; Jul [Epub ahead of print]. Suppliers a. Hologic, Inc, 35 Crosby Dr, Bedford, MA b. IDS Inc, E Enterprise Dr, Fountain Hills, AZ c. DPC Inc, 5210 Pacific Concourse Dr, Los Angeles, CA d. SPSS Inc, 233 S Wacker Dr, 11th Fl, Chicago, IL