Impact of Dietary Protein on Osteoporosis Development
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. Amount of Protein in the Diet and the Risk of Osteoporosis
3.2. Dietary Protein and Calcium Balance
3.3. Effect of Protein Supplementation on Bone Markers
3.4. Dairy Products in the Prevention and Treatment of Osteoporosis
3.5. Plant Protein in the Risk of Osteoporosis
3.6. Protein Supplementation Combined with Physical Activity
3.7. Dietary Protein Interventions and Bone Health in Eating Disorders
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Szczeklik, A.; Gajewski, P. Chapter: Osteoporoza. In Interna Szczeklika 2021, 12th ed.; Medycyna Praktyczna: Warszawa, Poland, 2021; pp. 2183–2191. (In Polish) [Google Scholar]
- Www.Cdc.Gov. Available online: https://www.cdc.gov/nchs/products/databriefs/db405.htm (accessed on 15 February 2022).
- Kanis, J.A.; Norton, N.; Harvey, N.C.; Jacobson, T.; Johansson, H.; Lorentzon, M.; McCloskey, E.V.; Willers, C.; Borgström, F. SCOPE 2021: A New Scorecard for Osteoporosis in Europe. Arch. Osteoporos. 2021, 16, 82. [Google Scholar] [CrossRef] [PubMed]
- Manolagas, S.C. Birth and Death of Bone Cells: Basic Regulatory Mechanisms and Implications for the Pathogenesis and Treatment of Osteoporosis. Endocr. Rev. 2000, 21, 115–137. [Google Scholar] [CrossRef] [PubMed]
- Odén, A.; McCloskey, E.V.; Kanis, J.A.; Harvey, N.C.; Johansson, H. Burden of High Fracture Probability Worldwide: Secular Increases 2010–2040. Osteoporos. Int. 2015, 26, 2243–2248. [Google Scholar] [CrossRef]
- Liu, C.; Kuang, X.; Li, K.; Guo, X.; Deng, Q.; Li, D. Effects of Combined Calcium and Vitamin D Supplementation on Osteoporosis in Postmenopausal Women: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Food Funct. 2020, 11, 10817–10827. [Google Scholar] [CrossRef] [PubMed]
- Weaver, C.M.; Alexander, D.D.; Boushey, C.J.; Dawson-Hughes, B.; Lappe, J.M.; LeBoff, M.S.; Liu, S.; Looker, A.C.; Wallace, T.C.; Wang, D.D. Calcium plus Vitamin D Supplementation and Risk of Fractures: An Updated Meta-Analysis from the National Osteoporosis Foundation. Osteoporos. Int. 2016, 27, 367–376. [Google Scholar] [CrossRef] [PubMed]
- Heaney, R.P. Effects of Protein on the Calcium Economy. Int. Congr. Ser. 2007, 1297, 191–197. [Google Scholar] [CrossRef]
- Shams-White, M.M.; Chung, M.; Fu, Z.; Insogna, K.L.; Karlsen, M.C.; LeBoff, M.S.; Shapses, S.A.; Sackey, J.; Shi, J.; Wallace, T.C.; et al. Animal versus Plant Protein and Adult Bone Health: A Systematic Review and Meta-Analysis from the National Osteoporosis Foundation. PLoS ONE 2018, 13, e0192459. [Google Scholar] [CrossRef]
- Arjmandi, B.H.; Khalil, D.A.; Smith, B.J.; Lucas, E.A.; Juma, S.; Payton, M.E.; Wild, R.A. Soy Protein Has a Greater Effect on Bone in Postmenopausal Women Not on Hormone Replacement Therapy, as Evidenced by Reducing Bone Resorption and Urinary Calcium Excretion. J. Clin. Endocrinol. Metab. 2003, 88, 1048–1054. [Google Scholar] [CrossRef]
- George, K.S.; Muñoz, J.; Akhavan, N.S.; Foley, E.M.; Siebert, S.C.; Tenenbaum, G.; Khalil, D.A.; Chai, S.C.; Arjmandi, B.H. Is Soy Protein Effective in Reducing Cholesterol and Improving Bone Health? Food Funct. 2020, 11, 544–551. [Google Scholar] [CrossRef]
- Haring, B.; Selvin, E.; Liang, M.; Coresh, J.; Grams, M.E.; Petruski-Ivleva, N.; Steffen, L.M.; Rebholz, C.M. Dietary Protein Sources and Risk for Incident Chronic Kidney Disease: Results from the Atherosclerosis Risk in Communities (ARIC) Study. J. Ren. Nutr. 2017, 27, 233–242. [Google Scholar] [CrossRef]
- Lew, Q.-L.J.; Jafar, T.H.; Koh, H.W.L.; Jin, A.; Chow, K.Y.; Yuan, J.-M.; Koh, W.-P. Red Meat Intake and Risk of ESRD. J. Am. Soc. Nephrol. 2017, 28, 304–312. [Google Scholar] [CrossRef] [PubMed]
- Trumbo, P.; Schlicker, S.; Yates, A.A.; Poos, M.; Food and Nutrition Board of the Institute of Medicine; The National Academies. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids. J. Am. Diet. Assoc. 2002, 102, 1621–1630. [Google Scholar] [CrossRef] [PubMed]
- Isanejad, M.; Sirola, J.; Mursu, J.; Kröger, H.; Tuppurainen, M.; Erkkilä, A.T. Association of Protein Intake with Bone Mineral Density and Bone Mineral Content among Elderly Women: The OSTPRE Fracture Prevention Study. J. Nutr. Health Aging 2017, 21, 622–630. [Google Scholar] [CrossRef]
- Heer, M.; Baecker, N.; Frings-Meuthen, P.; Graf, S.; Zwart, S.R.; Biolo, G.; Smith, S.M. Effects of High-Protein Intake on Bone Turnover in Long-Term Bed Rest in Women. Appl. Physiol. Nutr. Metab. 2017, 42, 537–546. [Google Scholar] [CrossRef]
- Pinheiro, M.B.; Oliveira, J.; Bauman, A.; Fairhall, N.; Kwok, W.; Sherrington, C. Evidence on Physical Activity and Osteoporosis Prevention for People Aged 65+ Years: A Systematic Review to Inform the WHO Guidelines on Physical Activity and Sedentary Behaviour. Int. J. Behav. Nutr. Phys. Act. 2020, 17, 150. [Google Scholar] [CrossRef] [PubMed]
- Wallace, T.C.; Frankenfeld, C.L. Dietary Protein Intake above the Current RDA and Bone Health: A Systematic Review and Meta-Analysis. J. Am. Coll. Nutr. 2017, 36, 481–496. [Google Scholar] [CrossRef]
- Beasley, J.M.; LaCroix, A.Z.; Larson, J.C.; Huang, Y.; Neuhouser, M.L.; Tinker, L.F.; Jackson, R.; Snetselaar, L.; Johnson, K.C.; Eaton, C.B.; 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. [Google Scholar] [CrossRef]
- Jennings, A.; MacGregor, A.; Spector, T.; Cassidy, A. Amino Acid Intakes Are Associated With Bone Mineral Density and Prevalence of Low Bone Mass in Women: Evidence From Discordant Monozygotic Twins. J. Bone Miner. Res. 2016, 31, 326–335. [Google Scholar] [CrossRef]
- Shams-White, M.M.; Chung, M.; Du, M.; Fu, Z.; Insogna, K.L.; Karlsen, M.C.; LeBoff, M.S.; Shapses, S.A.; Sackey, J.; Wallace, T.C.; et al. Dietary Protein and Bone Health: A Systematic Review and Meta-Analysis from the National Osteoporosis Foundation. Am. J. Clin. Nutr. 2017, 105, 1528–1543. [Google Scholar] [CrossRef]
- Fenton, T.R.; Lyon, A.W.; Eliasziw, M.; Tough, S.C.; Hanley, D.A. Meta-Analysis of the Effect of the Acid-Ash Hypothesis of Osteoporosis on Calcium Balance. J. Bone Miner. Res. 2009, 24, 1835–1840. [Google Scholar] [CrossRef]
- Kerstetter, J.E.; O’Brien, K.O.; Caseria, D.M.; Wall, D.E.; Insogna, K.L. The Impact of Dietary Protein on Calcium Absorption and Kinetic Measures of Bone Turnover in Women. J. Clin. Endocrinol. Metab. 2005, 90, 26–31. [Google Scholar] [CrossRef] [PubMed]
- Roughead, Z.K.; Johnson, L.K.; Lykken, G.I.; Hunt, J.R. Controlled High Meat Diets Do Not Affect Calcium Retention or Indices of Bone Status in Healthy Postmenopausal Women. J. Nutr. 2003, 133, 1020–1026. [Google Scholar] [CrossRef] [PubMed]
- Vasikaran, S.; Eastell, R.; Bruyère, O.; Foldes, A.J.; Garnero, P.; Griesmacher, A.; McClung, M.; Morris, H.A.; Silverman, S.; Trenti, T.; et al. Markers of Bone Turnover for the Prediction of Fracture Risk and Monitoring of Osteoporosis Treatment: A Need for International Reference Standards. Osteoporos. Int. 2011, 22, 391–420. [Google Scholar] [CrossRef] [PubMed]
- Islamoglu, A.H.; Garipagaoglu, M.; Bicer, H.S.; Kurtulus, D.; Ozturk, M.; Gunes, F.E. The Effects of Dietary Changes on Bone Markers in Postmenopausal Vertebral Osteopenia. Clin. Nutr. 2020, 39, 3744–3749. [Google Scholar] [CrossRef]
- Itkonen, S.T.; Päivärinta, E.; Pellinen, T.; Viitakangas, H.; Risteli, J.; Erkkola, M.; Lamberg-Allardt, C.; Pajari, A.-M. Partial Replacement of Animal Proteins with Plant Proteins for 12 Weeks Accelerates Bone Turnover Among Healthy Adults: A Randomized Clinical Trial. J. Nutr. 2021, 151, 11–19. [Google Scholar] [CrossRef] [PubMed]
- Crane, J.L.; Cao, X. Function of Matrix IGF-1 in Coupling Bone Resorption and Formation. J. Mol. Med. 2014, 92, 107–115. [Google Scholar] [CrossRef]
- Bonjour, J.-P.; Benoit, V.; Rousseau, B.; Souberbielle, J.-C. Consumption of Vitamin D-and Calcium-Fortified Soft White Cheese Lowers the Biochemical Marker of Bone Resorption TRAP 5b in Postmenopausal Women at Moderate Risk of Osteoporosis Fracture. J. Nutr. 2012, 142, 698–703. [Google Scholar] [CrossRef]
- Brown, A.; Leeds, A.R. Very Low-Energy and Low-Energy Formula Diets: Effects on Weight Loss, Obesity Comorbidities and Type 2 Diabetes Remission—An Update on the Evidence for Their Use in Clinical Practice. Nutr. Bull. 2019, 44, 7–24. [Google Scholar] [CrossRef]
- Murphy, C.; Bilek, L.D.D.; Koehler, K. Low Energy Availability with and without a High-Protein Diet Suppresses Bone Formation and Increases Bone Resorption in Men: A Randomized Controlled Pilot Study. Nutrients 2021, 13, 802. [Google Scholar] [CrossRef]
- Fabiani, R.; Naldini, G.; Chiavarini, M. Dietary Patterns in Relation to Low Bone Mineral Density and Fracture Risk: A Systematic Review and Meta-Analysis. Adv. Nutr. 2019, 10, 219–236. [Google Scholar] [CrossRef]
- Shi, Y.; Zhan, Y.; Chen, Y.; Jiang, Y. Effects of Dairy Products on Bone Mineral Density in Healthy Postmenopausal Women: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Arch. Osteoporos. 2020, 15, 48. [Google Scholar] [CrossRef] [PubMed]
- Balk, E.M.; Adam, G.P.; Langberg, V.N.; Earley, A.; Clark, P.; Ebeling, P.R.; Mithal, A.; Rizzoli, R.; Zerbini, C.A.F.; Pierroz, D.D.; et al. Global Dietary Calcium Intake among Adults: A Systematic Review. Osteoporos. Int. 2017, 28, 3315–3324. [Google Scholar] [CrossRef] [PubMed]
- Dawson-Hughes, B.; Harris, S.S.; Rasmussen, H.M.; Dallal, G.E. Comparative Effects of Oral Aromatic and Branched-Chain Amino Acids on Urine Calcium Excretion in Humans. Osteoporos. Int. 2007, 18, 955–961. [Google Scholar] [CrossRef] [PubMed]
- Manios, Y.; Moschonis, G.; Trovas, G.; Lyritis, G.P. Changes in Biochemical Indexes of Bone Metabolism and Bone Mineral Density after a 12-Mo Dietary Intervention Program: The Postmenopausal Health Study. Am. J. Clin. Nutr. 2007, 86, 781–789. [Google Scholar] [CrossRef] [PubMed]
- Rizzoli, R. Dairy Products, Yogurts, and Bone Health. Am. J. Clin. Nutr. 2014, 99, 1256S–1262S. [Google Scholar] [CrossRef] [PubMed]
- Malmir, H.; Larijani, B.; Esmaillzadeh, A. Consumption of Milk and Dairy Products and Risk of Osteoporosis and Hip Fracture: A Systematic Review and Meta-Analysis. Crit. Rev. Food Sci. Nutr. 2020, 60, 1722–1737. [Google Scholar] [CrossRef] [PubMed]
- Rizzo, G.; Baroni, L. Soy, Soy Foods and Their Role in Vegetarian Diets. Nutrients 2018, 10, 43. [Google Scholar] [CrossRef]
- Song, M.; Fung, T.T.; Hu, F.B.; Willett, W.C.; Longo, V.D.; Chan, A.T.; Giovannucci, E.L. Association of Animal and Plant Protein Intake With All-Cause and Cause-Specific Mortality. JAMA Intern. Med. 2016, 176, 1453–1463. [Google Scholar] [CrossRef]
- Kunutsor, S.K.; Leyland, S.; Skelton, D.A.; James, L.; Cox, M.; Gibbons, N.; Whitney, J.; Clark, E.M. Adverse Events and Safety Issues Associated with Physical Activity and Exercise for Adults with Osteoporosis and Osteopenia: A Systematic Review of Observational Studies and an Updated Review of Interventional Studies. J. Frailty Sarcopenia Falls 2018, 3, 155–178. [Google Scholar] [CrossRef]
- Lambert, M.N.T.; Hu, L.M.; Jeppesen, P.B. A Systematic Review and Meta-Analysis of the Effects of Isoflavone Formulations against Estrogen-Deficient Bone Resorption in Peri- and Postmenopausal Women. Am. J. Clin. Nutr. 2017, 106, 801–811. [Google Scholar] [CrossRef]
- Akhlaghi, M.; Ghasemi Nasab, M.; Riasatian, M.; Sadeghi, F. Soy Isoflavones Prevent Bone Resorption and Loss, a Systematic Review and Meta-Analysis of Randomized Controlled Trials. Crit. Rev. Food Sci. Nutr. 2020, 60, 2327–2341. [Google Scholar] [CrossRef] [PubMed]
- Li, L.; Sun, M.; Sun, J.; Kong, H.; Zhong, W.; Wang, H. The Effect of Dried Beancurd on Bone Mineral Density in Postmenopausal Chinese Women: A 2-Year Randomized Controlled Trial. Calcif. Tissue Int. 2019, 105, 573–581. [Google Scholar] [CrossRef] [PubMed]
- Exercise Interventions: Defusing the World’s Osteoporosis Time Bomb—PubMed. Available online: https://pubmed.ncbi.nlm.nih.gov/14758410/ (accessed on 14 June 2022).
- Wright, C.S.; McMorrow, A.M.; Weinheimer-Haus, E.M.; Campbell, W.W. Whey Protein Supplementation and Higher Total Protein Intake Do Not Influence Bone Quantity in Overweight and Obese Adults Following a 36-Week Exercise and Diet Intervention1234. J. Nutr. 2017, 147, 179–186. [Google Scholar] [CrossRef] [PubMed]
- Shenoy, S.; Bedi, R.; Sandhu, J.S. Effect of Soy Isolate Protein and Resistance Exercises on Muscle Performance and Bone Health of Osteopenic/Osteoporotic Postmenopausal Women. J. Women Aging 2013, 25, 183–198. [Google Scholar] [CrossRef] [PubMed]
- Fassio, A.; Idolazzi, L.; Rossini, M.; Gatti, D.; Adami, G.; Giollo, A.; Viapiana, O. The Obesity Paradox and Osteoporosis. Eat. Weight. Disord. 2018, 23, 293–302. [Google Scholar] [CrossRef] [PubMed]
- Caroline, M.; Apovian, M.D. Obesity: Definition, Comorbidities, Causes, and Burden. Am. J. Manag. Care 2016, 22, S176–S185. [Google Scholar]
- Weaver, A.A.; Houston, D.K.; Shapses, S.A.; Lyles, M.F.; Henderson, R.M.; Beavers, D.P.; Baker, A.C.; Beavers, K.M. Effect of a Hypocaloric, Nutritionally Complete, Higher-Protein Meal Plan on Bone Density and Quality in Older Adults with Obesity: A Randomized Trial. Am. J. Clin. Nutr. 2019, 109, 478–486. [Google Scholar] [CrossRef]
- Wright, C.S.; Li, J.; Campbell, W.W. Effects of Dietary Protein Quantity on Bone Quantity following Weight Loss: A Systematic Review and Meta-Analysis. Adv. Nutr. 2019, 10, 1089–1107. [Google Scholar] [CrossRef]
- Gkastaris, K.; Goulis, D.G.; Potoupnis, M.; Anastasilakis, A.D.; Kapetanos, G. Obesity, Osteoporosis and Bone Metabolism. J. Musculoskelet. Neuronal Interact. 2020, 20, 372–381. [Google Scholar]
- Shapses, S.A.; Sukumar, D. Bone Metabolism in Obesity and Weight Loss. Annu. Rev. Nutr. 2012, 32, 287–309. [Google Scholar] [CrossRef]
- Robinson, L.; Aldridge, V.; Clark, E.M.; Misra, M.; Micali, N. A Systematic Review and Meta-Analysis of the Association between Eating Disorders and Bone Density. Osteoporos. Int. 2016, 27, 1953–1966. [Google Scholar] [CrossRef] [PubMed]
- Solmi, M.; Veronese, N.; Correll, C.U.; Favaro, A.; Santonastaso, P.; Caregaro, L.; Vancampfort, D.; Luchini, C.; De Hert, M.; Stubbs, B. Bone Mineral Density, Osteoporosis, and Fractures among People with Eating Disorders: A Systematic Review and Meta-Analysis. Acta Psychiatr. Scand. 2016, 133, 341–351. [Google Scholar] [CrossRef] [PubMed]
- Zipfel, S.; Seibel, M.J.; Löwe, B.; Beumont, P.J.; Kasperk, C.; Herzog, W. Osteoporosis in Eating Disorders: A Follow-up Study of Patients with Anorexia and Bulimia Nervosa. J. Clin. Endocrinol. Metab. 2001, 86, 5227–5233. [Google Scholar] [CrossRef] [PubMed]
- Kerstetter, J.E.; Bihuniak, J.D.; Brindisi, J.; Sullivan, R.R.; Mangano, K.M.; Larocque, S.; Kotler, B.M.; Simpson, C.A.; Cusano, A.M.; Gaffney-Stomberg, E.; et al. The Effect of a Whey Protein Supplement on Bone Mass in Older Caucasian Adults. J. Clin. Endocrinol. Metab. 2015, 100, 2214–2222. [Google Scholar] [CrossRef]
- Barrionuevo, P.; Kapoor, E.; Asi, N.; Alahdab, F.; Mohammed, K.; Benkhadra, K.; Almasri, J.; Farah, W.; Sarigianni, M.; Muthusamy, K.; et al. Efficacy of Pharmacological Therapies for the Prevention of Fractures in Postmenopausal Women: A Network Meta-Analysis. J. Clin. Endocrinol. Metab. 2019, 104, 1623–1630. [Google Scholar] [CrossRef]
- Huhmann, K. Menses Requires Energy: A Review of How Disordered Eating, Excessive Exercise, and High Stress Lead to Menstrual Irregularities. Clin. Ther. 2020, 42, 401–407. [Google Scholar] [CrossRef]
- Sefton, J.M.; Lyons, K.D.; Beck, D.T.; Haun, C.T.; Romero, M.A.; Mumford, P.W.; Roberson, P.A.; Young, K.C.; Roberts, M.D.; McAdam, J.S. Markers of Bone Health and Impact of Whey Protein Supplementation in Army Initial Entry Training Soldiers: A Double-Blind Placebo-Controlled Study. Nutrients 2020, 12, 2225. [Google Scholar] [CrossRef]
- Nève, G.; Bur, L.; Lampert, L.; Höchsmann, C.; Brombach, C.; Steinemann, N.; Schmidt-Trucksäss, A. Validation of a Visually Aided Dietary Assessment Tool to Estimate Dietary Intake in an Adult Swiss Population. Front. Nutr. 2022, 9, 844156. [Google Scholar] [CrossRef]
Impact of Dairy Product Consumption on BMD and Osteoporotic Fracture | |||||
---|---|---|---|---|---|
Author | N—Number of Included Studies | Year of Study | n—Number of Patients | Results of Meta-Analysis | Characteristics of the Analyzed Population |
Shi et al., 2020 [33] | N = 6 | 1995 to 2012 | n = 618 | Dairy products => ↑ BMD and plays an important role in the prevention of osteoporosis after menopause. | Healthy postmenopausal women |
Fabiani et al., 2019 [32] | N = 20 (total) N =10 (fracture risk) N = 10 (low BMD risk) | 2010 to 2017 | n = 276,624 (total) n = 257,010 (fracture risk) n = 19,614 (low BMD risk) | “Milk/dairy” and “healthy” dietary patterns => ↓ risk of low BMD “healthy” pattern => ↓ risk of fracture. “Meat/western” dietary pattern => ↑ risk of low BMD and fracture BMD. | Youth >10 years old and adults |
Malmir et al., 2020 [38] | N = 34 (total) N = 13 (osteoporosis) N = 21 (hip fracture) | 1989 to 2018 | n = 431,545 (total): n = 9641 (osteoporosis) n = 11,904 (hip fracture) | ↑ intake of dairy products does not reduce the risk of osteoporosis and hip fracture. | Adults (>18 years old) |
Lifestyle Changes in Patients with Osteoporosis | ||
---|---|---|
Recommendations | Study Conformation/Scientific Proof | References |
Plant and animal protein |
| [9] [27] [38] [15,16] |
Soy products |
| [39] |
Nuts, soy, legumes, fish, poultry, and eggs |
| [12,13] |
Poultry, low-fat dairy, fish, soy, and legumes |
| [40] |
Adequate to age physical activity |
| [17] [41] [15] |
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Kędzia, G.; Woźniak, M.; Samborski, W.; Grygiel-Górniak, B. Impact of Dietary Protein on Osteoporosis Development. Nutrients 2023, 15, 4581. https://doi.org/10.3390/nu15214581
Kędzia G, Woźniak M, Samborski W, Grygiel-Górniak B. Impact of Dietary Protein on Osteoporosis Development. Nutrients. 2023; 15(21):4581. https://doi.org/10.3390/nu15214581
Chicago/Turabian StyleKędzia, Gabriela, Martyna Woźniak, Włodzimierz Samborski, and Bogna Grygiel-Górniak. 2023. "Impact of Dietary Protein on Osteoporosis Development" Nutrients 15, no. 21: 4581. https://doi.org/10.3390/nu15214581
APA StyleKędzia, G., Woźniak, M., Samborski, W., & Grygiel-Górniak, B. (2023). Impact of Dietary Protein on Osteoporosis Development. Nutrients, 15(21), 4581. https://doi.org/10.3390/nu15214581