Preprint / Version 1

Protein intake is associated with lean mass and femur bone mass in individuals with rheumatic diseases from the NHANES cohort


  • Gabriel Perri Esteves Applied Physiology and Nutrition Research Group - Center of Lifestyle Medicine, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, BR
  • Paul Swinton School of Health Sciences, Robert Gordon University, Aberdeen, UK
  • Craig Sale Institute of Sport, Manchester Metropolitan University, Manchester, UK
  • Hamilton Roschel Applied Physiology and Nutrition Research Group - Center of Lifestyle Medicine, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, BR
  • Bruno Gualano Applied Physiology and Nutrition Research Group - Center of Lifestyle Medicine, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, BR
  • Eimear Dolan Applied Physiology and Nutrition Research Group - Center of Lifestyle Medicine, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, BR



rheumatic conditions, lifestyle, dietary habits, musculoskeletal health, glucocorticoid therapy


Background/Objectives: Strategies to protect musculoskeletal health in individuals with rheumatic diseases (RDs) are of utmost importance. Optimizing protein intake is one such potential strategy. The aim of this investigation was to explore the relationship between protein intake and muscle and bone masses in individuals with rheumatic diseases, using data from the NHANES database.

Method: Relevant data were extracted from six NHANES cycles, providing a total sample of 4,122 individuals with varying RDs (psoriatic arthritis, rheumatoid arthritis, osteoarthritis and gout). Potential confounding variables and their relationship to outcomes of interest were visualized using directed acyclic graphs. Outcomes of interest were lean and bone mass, measured at the whole-body, femur and lumbar spine by DXA. Multivariable regression models adjusted for potential confounding variables (body mass, sex, age, disease category and total caloric intake) were used.

Results: There was a small positive association between protein intake and muscle mass, both when protein was considered in absolute values (grams) (β=0.08 (95%CI 0.04-0.14), p-value=0.0002) or when relative to body mass (g/kgBM/d) (β=0.05 (95%CI 0.02-0.08), p-value=0.0036). A positive relationship was also shown between protein intake and femur BMD, but only when protein was considered in absolute values (β=0.08 (95%CI 0.03-0.14), p-value=0.0024).  

Conclusion: Protein intake might have a relevant role in improving muscle, and potentially bone, mass in individuals with RD, although effects seem to be small. These findings pave the way for future randomized controlled trials to assess the role of increased protein intake on bone and muscle mass in patients with RD.


Metrics Loading ...


Szekanecz Z, McInnes IB, Schett G, Szamosi S, Benkő S, Szűcs G. Autoinflammation and autoimmunity across rheumatic and musculoskeletal diseases. Nat Rev Rheumatol (2021) 17:585–595. doi: 10.1038/s41584-021-00652-9

Aletaha D, Smolen JS. Diagnosis and Management of Rheumatoid Arthritis. JAMA (2018) 320:1360. doi: 10.1001/jama.2018.13103

Fanouriakis A, Bertsias G. Changing paradigms in the treatment of systemic lupus erythematosus. Lupus Sci Med (2019) 6:e000310. doi: 10.1136/lupus-2018-000310

van der Goes MC, Jacobs JW, Bijlsma JW. The value of glucocorticoid co-therapy in different rheumatic diseases--positive and adverse effects. Arthritis Res Ther (2014) 16 Suppl 2:S2. doi: 10.1186/ar4686

Machado-Alba JE, Ruiz AF, Machado-Duque ME. Adverse drug reactions associated with the use of disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis. Rev Panam Salud Publica (2014) 36:396–401.

de Camargo MC, Barros BCA, Fulone I, Silva MT, Silveira MS do N, Camargo IA de, Barberato-Filho S, del Fiol F de S, Lopes LC. Adverse Events in Patients With Rheumatoid Arthritis and Psoriatic Arthritis Receiving Long-Term Biological Agents in a Real-Life Setting. Front Pharmacol (2019) 10: doi: 10.3389/fphar.2019.00965

Fardet L, Petersen I, Nazareth I. Risk of cardiovascular events in people prescribed glucocorticoids with iatrogenic Cushing’s syndrome: cohort study. BMJ (2012) 345:e4928–e4928. doi: 10.1136/bmj.e4928

Fardet L, Cabane J, Kettaneh A, Lebbe C, Flahault A. Corticosteroid-induced lipodystrophy is associated with features of the metabolic syndrome. Rheumatology (2007) 46:1102–1106. doi: 10.1093/rheumatology/kem062

Compston J. Glucocorticoid-induced osteoporosis: an update. Endocrine (2018) 61:7–16. doi: 10.1007/s12020-018-1588-2

Pereira RMR, Freire de Carvalho J. Glucocorticoid-induced myopathy. Joint Bone Spine (2011) 78:41–44. doi: 10.1016/j.jbspin.2010.02.025

Nussinovitch U, Freire de Carvalho J, Maria R. Pereira R, Shoenfeld Y. Glucocorticoids and the Cardiovascular System: State of the Art. Curr Pharm Des (2010) 16:3574–3585. doi: 10.2174/138161210793797870

Pereira RMR, Perez MO, Paula AP, Moreira C, Castro CHM, Zerbini CAF, Domiciano DS, de Azevedo E, Mendonca LMC, Shinzato MM, et al. Guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis: an update of Brazilian Society of Rheumatology (2020). Arch Osteoporos (2021) 16:49. doi: 10.1007/s11657-021-00902-z

Wilson JC, Sarsour K, Gale S, Pethö‐Schramm A, Jick SS, Meier CR. Incidence and Risk of Glucocorticoid‐Associated Adverse Effects in Patients With Rheumatoid Arthritis. Arthritis Care Res (Hoboken) (2019) 71:498–511. doi: 10.1002/acr.23611

Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, Siu S, Kraft J, Lynde C, Pope J, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis (2015) 74:480–489. doi: 10.1136/annrheumdis-2014-206624

Esteves GP, Mazzolani BC, Smaira FI, Mendes ES, de Oliveira GG, Roschel H, Gualano B, Pereira RMR, Dolan E. Nutritional recommendations for patients undergoing prolonged glucocorticoid therapy. Rheumatol Adv Pract (2022) doi: 10.1093/rap/rkac029

Rausch Osthoff A-K, Niedermann K, Braun J, Adams J, Brodin N, Dagfinrud H, Duruoz T, Esbensen BA, Günther K-P, Hurkmans E, et al. 2018 EULAR recommendations for physical activity in people with inflammatory arthritis and osteoarthritis. Ann Rheum Dis (2018) 77:1251–1260. doi: 10.1136/annrheumdis-2018-213585

Perandini L, Sales de Oliveira D, Mello S, Camara N, Benatti F, Lima F, Borba E, Bonfa E, Sa-Pinto A, Roschel H, et al. Exercise training can attenuate the inflammatory milieu in women with systemic lupus erythematosus. J Appl Physiol (2014) 117:639–47.

Benatti F, Miyake C, Dantas W, Zambelli V, Shinjo S, Pereira R, Silva M, Sa-Pinto A, Borba E, Bonfa E, et al. Exercise Increases Insulin Sensitivity and Skeletal Muscle AMPK Expression in Systemic Lupus Erythematosus: A Randomized Controlled Trial. Front Immunol (2018) 9:906.

Prado D, Benatti F, de Sa-Pinto A, Hayashi A, Gualano B, Pereira R, Sallum A, Bonfa E, Silva C, Roschel H. Exercise training in childhood-onset systemic lupus erythematosus: a controlled randomized trial. Arthritis Res Ther (2013) 15:R46.

Gualano B, Bonfa E, Pereira RMRR, Silva CA. Physical activity for paediatric rheumatic diseases: standing up against old paradigms. Nat Rev Rheumatol (2017) 13:368–379. doi: 10.1038/nrrheum.2017.75

Minetto MA, Qaisar R, Agoni V, Motta G, Longa E, Miotti D, Pellegrino MA, Bottinelli R. Quantitative and qualitative adaptations of muscle fibers to glucocorticoids. Muscle Nerve (2015) 52:631–639. doi: 10.1002/mus.24572

Yamada Y, Tada M, Mandai K, Hidaka N, Inui K, Nakamura H. Glucocorticoid use is an independent risk factor for developing sarcopenia in patients with rheumatoid arthritis: from the CHIKARA study. Clin Rheumatol (2020) 39:1757–1764. doi: 10.1007/s10067-020-04929-4

Dalbeth N, Petrie KJ, House M, Chong J, Leung W, Chegudi R, Horne A, Gamble G, McQueen FM, Taylor WJ. Illness perceptions in patients with gout and the relationship with progression of musculoskeletal disability. Arthritis Care Res (Hoboken) (2011) 63:1605–1612. doi: 10.1002/acr.20570

Kanis JA, Johansson H, Oden A, Johnell O, de Laet C, Melton LJ, Tenenhouse A, Reeve J, Silman AJ, Pols HA, et al. A Meta-Analysis of Prior Corticosteroid Use and Fracture Risk. Journal of Bone and Mineral Research (2004) 19:893–899. doi: 10.1359/JBMR.040134

Bultink IEM, Lems WF. Osteoarthritis and Osteoporosis: What Is the Overlap? Curr Rheumatol Rep (2013) 15:328. doi: 10.1007/s11926-013-0328-0

Liao C, Chen H, Kuo Y, Tsauo J, Huang S, Liou T. Effects of Muscle Strength Training on Muscle Mass Gain and Hypertrophy in Older Adults With Osteoarthritis: A Systematic Review and Meta‐Analysis. Arthritis Care Res (Hoboken) (2020) 72:1703–1718. doi: 10.1002/acr.24097

Woolf AD. Global burden of osteoarthritis and musculoskeletal diseases. BMC Musculoskelet Disord (2015) 16:S3. doi: 10.1186/1471-2474-16-S1-S3

Woolf AD, Vos T, March L. How to measure the impact of musculoskeletal conditions. Best Pract Res Clin Rheumatol (2010) 24:723–732. doi: 10.1016/j.berh.2010.11.002

Jin S, Hsieh E, Peng L, Yu C, Wang Y, Wu C, Wang Q, Li M, Zeng X. Incidence of fractures among patients with rheumatoid arthritis: a systematic review and meta-analysis. Osteoporosis International (2018) 29:1263–1275. doi: 10.1007/s00198-018-4473-1

Xue A-L, Wu S-Y, Jiang L, Feng A-M, Guo H-F, Zhao P. Bone fracture risk in patients with rheumatoid arthritis. Medicine (2017) 96:e6983. doi: 10.1097/MD.0000000000006983

van Staa TP, Leufkens HGM, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: A meta-analysis. Osteoporosis International (2002) 13:777–787. doi: 10.1007/s001980200108

LoCascio V, Bonucci E, Imbimbo B, Ballanti P, Adami S, Milani S, Tartarotti D, DellaRocca C. Bone loss in response to long-term glucocorticoid therapy. Bone Miner (1990) 8:39–51. doi: 10.1016/0169-6009(91)90139-Q

Chotiyarnwong P, McCloskey E v. Pathogenesis of glucocorticoid-induced osteoporosis and options for treatment. Nat Rev Endocrinol (2020) 16:437–447. doi: 10.1038/s41574-020-0341-0

Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, Cooper C, Landi F, Rolland Y, Sayer AA, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing (2019) 48:16–31. doi: 10.1093/ageing/afy169

Torii M, Hashimoto M, Hanai A, Fujii T, Furu M, Ito H, Uozumi R, Hamaguchi M, Terao C, Yamamoto W, et al. Prevalence and factors associated with sarcopenia in patients with rheumatoid arthritis. Mod Rheumatol (2019) 29:589–595. doi: 10.1080/14397595.2018.1510565

Wiegmann S, Armbrecht G, Borucki D, Buehring B, Buttgereit F, Detzer C, Schaumburg D, Zeiner KN, Dietzel R. Association between sarcopenia, physical performance and falls in patients with rheumatoid arthritis: a 1-year prospective study. BMC Musculoskelet Disord (2021) 22:885. doi: 10.1186/s12891-021-04605-x

Stanmore EK, Oldham J, Skelton DA, O’Neill T, Pilling M, Campbell AJ, Todd C. Fall Incidence and Outcomes of Falls in a Prospective Study of Adults With Rheumatoid Arthritis. Arthritis Care Res (Hoboken) (2013) 65:737–744. doi: 10.1002/acr.21892

Brenton-Rule A, Dalbeth N, Bassett S, Menz HB, Rome K. The incidence and risk factors for falls in adults with rheumatoid arthritis: A systematic review. Semin Arthritis Rheum (2015) 44:389–398. doi: 10.1016/j.semarthrit.2014.08.001

Deutz NEP, Bauer JM, Barazzoni R, Biolo G, Boirie Y, Bosy-Westphal A, Cederholm T, Cruz-Jentoft A, Krznariç Z, Nair KS, et al. Protein intake and exercise for optimal muscle function with aging: Recommendations from the ESPEN Expert Group. Clinical Nutrition (2014) 33:929–936. doi: 10.1016/j.clnu.2014.04.007

Arends J, Bachmann P, Baracos V, Barthelemy N, Bertz H, Bozzetti F, Fearon K, Hütterer E, Isenring E, Kaasa S, et al. ESPEN guidelines on nutrition in cancer patients. Clinical Nutrition (2017) 36:11–48. doi: 10.1016/j.clnu.2016.07.015

Sherman HC, Rose AR, Rose MS. CALCIUM REQUIREMENT OF MAINTENANCE IN MAN. Journal of Biological Chemistry (1920) 44:21–27. doi: 10.1016/S0021-9258(18)86268-8

Dolan E, Sale C. Protein and bone health across the lifespan. Proceedings of the Nutrition Society (2019) 78:45–55. doi: 10.1017/S0029665118001180

Wallace TCC, Frankenfeld CLL. Dietary Protein Intake above the Current RDA and Bone Health: A Systematic Review and Meta-Analysis. J Am Coll Nutr (2017) 36:481–496. doi: 10.1080/07315724.2017.1322924

Shams-White MM, Chung M, Du M, Fu Z, Insogna KL, Karlsen MC, LeBoff MS, Shapses SA, Sackey J, Wallace TC, et al. Dietary protein and bone health: a systematic review and meta-analysis from the National Osteoporosis Foundation. Am J Clin Nutr (2017)ajcn145110. doi: 10.3945/ajcn.116.145110

Wu A-M, Sun X-L, Lv Q-B, Zhou Y, Xia D-D, Xu H-Z, Huang Q-S, Chi Y-L. The Relationship between Dietary Protein Consumption and Risk of Fracture: a subgroup and dose-response meta-analysis of prospective cohort studies. Sci Rep (2015) 5:9151. doi: 10.1038/srep09151

Nunes EA, Colenso‐Semple L, McKellar SR, Yau T, Ali MU, Fitzpatrick‐Lewis D, Sherifali D, Gaudichon C, Tomé D, Atherton PJ, et al. Systematic review and meta‐analysis of protein intake to support muscle mass and function in healthy adults. J Cachexia Sarcopenia Muscle (2022) 13:795–810. doi: 10.1002/jcsm.12922

Rizzoli R, Biver E, Bonjour J, Coxam V, Goltzman D, Kanis JA, Lappe J, Rejnmark L, Sahni S. Benefits and safety of dietary protein for bone health — an expert consensus paper endorsed by the European Society for Clinical and Economical Aspects of Osteopororosis , Osteoarthritis , and Musculoskeletal Diseases and by the International Osteoporosis. Osteoporosis International (2018) 29:1933–48.

Buckinx F, Landi F, Cesari M, Fielding RA, Visser M, Engelke K, Maggi S, Dennison E, Al-Daghri NM, Allepaerts S, et al. Pitfalls in the measurement of muscle mass: a need for a reference standard. J Cachexia Sarcopenia Muscle (2018) 9:269–278. doi: 10.1002/jcsm.12268

Center for Disease Control. National Health and Nutrition Examination Survey (NHANES) Body Composition Procedures Manual. (2018)

CDC/National Center for Health Statistics. NHANES Questionnaire Instruments. NHANES Questionnaire Instruments (2018) [Accessed September 18, 2022]

Tennant PWG, Murray EJ, Arnold KF, Berrie L, Fox MP, Gadd SC, Harrison WJ, Keeble C, Ranker LR, Textor J, et al. Use of directed acyclic graphs (DAGs) to identify confounders in applied health research: review and recommendations. Int J Epidemiol (2021) 50:620–632. doi: 10.1093/ije/dyaa213

Papageorgiou M, Martin D, Colgan H, Cooper S, Greeves JP, Tang JCY, Fraser WD, Elliott-Sale KJ, Sale C. Bone metabolic responses to low energy availability achieved by diet or exercise in active eumenorrheic women. Bone (2018) 114:181–188. doi: 10.1016/j.bone.2018.06.016

Tomova GD, Arnold KF, Gilthorpe MS, Tennant PWG. Adjustment for energy intake in nutritional research: a causal inference perspective. Am J Clin Nutr (2022) 115:189–198. doi: 10.1093/ajcn/nqab266

CDC/National Center for Health Statistics. NHANES Survey Methods and Analytic Guidelines. (2022)

Lumley T. Analysis of Complex Survey Samples. J Stat Softw (2004) 9: doi: 10.18637/jss.v009.i08

Phillips SM, Chevalier S, Leidy HJ. Protein “requirements” beyond the RDA: implications for optimizing health. Applied Physiology, Nutrition, and Metabolism (2016) 41:565–572. doi: 10.1139/apnm-2015-0550

Tipton KD, Ferrando AA, Phillips SM, Doyle D, Wolfe RR. Postexercise net protein synthesis in human muscle from orally administered amino acids. American Journal of Physiology-Endocrinology and Metabolism (1999) 276:E628–E634. doi: 10.1152/ajpendo.1999.276.4.E628

Volpi E, Ferrando AA, Yeckel CW, Tipton KD, Wolfe RR. Exogenous amino acids stimulate net muscle protein synthesis in the elderly. Journal of Clinical Investigation (1998) 101:2000–2007. doi: 10.1172/JCI939

Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C., D.C.: National Academies Press (2005). doi: 10.17226/10490

Burd NA, Gorissen SH, van Loon LJC. Anabolic Resistance of Muscle Protein Synthesis with Aging. Exerc Sport Sci Rev (2013) 41:169–173. doi: 10.1097/JES.0b013e318292f3d5

Rennie MJ. Anabolic resistance in critically ill patients. Crit Care Med (2009) 37:S398–S399. doi: 10.1097/CCM.0b013e3181b6ec1f

Durham WJ, Dillon EL, Sheffield-Moore M. Inflammatory burden and amino acid metabolism in cancer cachexia. Curr Opin Clin Nutr Metab Care (2009) 12:72–77. doi: 10.1097/MCO.0b013e32831cef61

Troncoso R, Paredes F, Parra V, Gatica D, Vásquez-Trincado C, Quiroga C, Bravo-Sagua R, Loṕez-Crisosto C, Rodriguez AE, Oyarzuń AP, et al. Dexamethasone-induced autophagy mediates muscle atrophy through mitochondrial clearance. Cell Cycle (2014) 13:2281–2295. doi: 10.4161/cc.29272

Rafii M, Chapman K, Owens J, Elango R, Campbell WW, Ball RO, Pencharz PB, Courtney-Martin G. Dietary Protein Requirement of Female Adults >65 Years Determined by the Indicator Amino Acid Oxidation Technique Is Higher Than Current Recommendations. J Nutr (2015) 145:18–24. doi: 10.3945/jn.114.197517

Tang M, McCabe GP, Elango R, Pencharz PB, Ball RO, Campbell WW. Assessment of protein requirement in octogenarian women with use of the indicator amino acid oxidation technique. Am J Clin Nutr (2014) 99:891–898. doi: 10.3945/ajcn.112.042325

Heaney RP. Effects of protein on the calcium economy. Int Congr Ser (2007) 1297:191–197. doi: 10.1016/j.ics.2006.08.025

THISSEN J-P, KETELSLEGERS J-M, UNDERWOOD LE. Nutritional Regulation of the Insulin-Like Growth Factors*. Endocr Rev (1994) 15:80–101. doi: 10.1210/edrv-15-1-80

Mangano KM, Sahni S, Kiel DP, Tucker KL, Dufour AB, Hannan MT. Bone Mineral Density and Protein-Derived Food Clusters from the Framingham Offspring Study. J Acad Nutr Diet (2015) 115:1605-1613.e1. doi: 10.1016/j.jand.2015.04.001

Benedetti MG, Furlini G, Zati A, Letizia Mauro G. The Effectiveness of Physical Exercise on Bone Density in Osteoporotic Patients. Biomed Res Int (2018) 2018:1–10. doi: 10.1155/2018/4840531

Kirwan RP, Mazidi M, Rodríguez García C, Lane KE, Jafari A, Butler T, Perez de Heredia F, Davies IG. Protein interventions augment the effect of resistance exercise on appendicular lean mass and handgrip strength in older adults: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr (2022) 115:897–913. doi: 10.1093/ajcn/nqab355

Volpi E, Nazemi R, Fujita S. Muscle tissue changes with aging. Curr Opin Clin Nutr Metab Care (2004) 7:405–410. doi: 10.1097/01.mco.0000134362.76653.b2

Beasley JM, LaCroix AZ, Larson JC, Huang Y, Neuhouser ML, Tinker LF, Jackson R, Snetselaar L, Johnson KC, Eaton CB, et al. Biomarker-calibrated protein intake and bone health in the Women’s Health Initiative clinical trials and observational study. Am J Clin Nutr (2014) 99:934–940. doi: 10.3945/ajcn.113.076786

Sahni S, Broe KE, Tucker KL, McLean RR, Kiel DP, Cupples LA, Hannan MT. Association of total protein intake with bone mineral density and bone loss in men and women from the Framingham Offspring Study. Public Health Nutr (2014) 17:2570–2576. doi: 10.1017/S1368980013002875

Gibson RS, Charrondiere UR, Bell W. Measurement Errors in Dietary Assessment Using Self-Reported 24-Hour Recalls in Low-Income Countries and Strategies for Their Prevention. Advances in Nutrition: An International Review Journal (2017) 8:980–991. doi: 10.3945/an.117.016980