Osteoporosis: definition, diagnosis, and considerations prior to starting treatment

Abstract

Osteoporosis is a disabling disease with a significant impact on the global population, particularly among older men and postmenopausal women. Several factors contribute to the increasing prevalence of osteoporosis, including greater life expectancy and the absence of symptoms in its early stages. The morbidity, mortality, and substantial economic burden associated with osteoporosis, especially due to hip fractures and related complications, constitute a major public health concern. Diagnosis should involve a comprehensive biochemical profile, along with additional tests to rule out secondary causes, which are often underdiagnosed and can influence the progression of the disease. Preventive measures and early diagnosis are essential to maintaining bone health and preventing fractures and disability. This review will focus on the definition, diagnostic approach, and key considerations prior to initiating treatment in patients with osteoporosis. Fracture risk prediction tools, including Fracture Risk Assessment Tool (FRAX), and treatment strategies are not addressed, as this review focuses on the appropriate diagnostic evaluation of osteoporosis and the systematic exclusion of secondary causes.

Keywords

osteoporosis / bone mass / bone microarchitecture / fractures / DXA

References

[1] Vidal M, Thibodaux RJ, Neira LFV, Messina OD. Osteoporosis: a clinical and pharmacological update. Clin Rheumatol. 2019; 38: 385-95.

[2] Sözen T, Özışık L, Başaran NÇ. An overview and management of osteoporosis. Eur J Rheumatol. 2017; 4: 46-56.

[3] Maldonado G, Intriago M, Larroude M, Aguilar G, Moreno M, Gonzalez J, et al. Common errors in dual-energy X-ray absorptiometry scans in imaging centers in Ecuador. Arch Osteoporos. 2020; 15: 6.

[4] Slart RHJA, Punda M, Ali DS, Bazzocchi A, Bock O, Camacho P, et al.; International Working Group on DXA Best Practices. Updated practice guideline for dual-energy X-ray absorptiometry (DXA). Eur J Nucl Med Mol Imaging. 2025; 52: 539-63.

[5] GBD 2019 Fracture Collaborators. Global, regional, and national burden of bone fractures in 204 countries and territories, 1990-2019: a systematic analysis from the Global Burden of Disease Study 2019. Lancet Healthy Longev. 2021; 2: e580-92.

[6] Kanis JA, Johnell O, Oden A, Sembo I, Redlund-Johnell I, Dawson A, et al. Long-term risk of osteoporotic fracture in Malmö. Osteoporos Int. 2000; 11: 669-74.

[7] Melton LJ 3rd, Atkinson EJ, O’Connor MK, O’Fallon WM, Riggs BL. Bone density and fracture risk in men. J Bone Miner Res. 1998; 13: 1915-23.

[8] Melton LJ 3rd, Chrischilles EA, Cooper C, Lane AW, Riggs BL. Perspective. How many women have osteoporosis? J Bone Miner Res. 1992; 7: 1005-10.

[9] Curtis EM, van der Velde R, Moon RJ, van den Bergh JP, Geusens P, de Vries F, et al. Epidemiology of fractures in the United Kingdom 1988-2012: Variation with age, sex, geography, ethnicity and socioeconomic status. Bone. 2016; 87: 19-26.

[10] Naso CM, Lin SY, Song G, Xue H. Time trend analysis of osteoporosis prevalence among adults 50 years of age and older in the USA, 2005-2018. Osteoporos Int. 2025; 36: 547-54.

[11] Salari N, Ghasemi H, Mohammadi L, Behzadi MH, Rabieenia E, Shohaimi S, et al. The global prevalence of osteoporosis in the world: a comprehensive systematic review and meta-analysis. J Orthop Surg Res. 2021; 16: 609.

[12] Xiao PL, Cui AY, Hsu CJ, Peng R, Jiang N, Xu XH, et al. Global, regional prevalence, and risk factors of osteoporosis according to the World Health Organization diagnostic criteria: a systematic review and meta-analysis. Osteoporos Int. 2022; 33: 2137-53.

[13] Ballane G, Cauley JA, Luckey MM, Fuleihan GE. Secular trends in hip fractures worldwide: opposing trends East versus West. J Bone Miner Res. 2014; 29: 1745-55.

[14] Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA 3rd, Berger M. Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis. J Bone Miner Res. 2000; 15: 721-39.

[15] Melton LJ 3rd, Kearns AE, Atkinson EJ, Bolander ME, Achenbach SJ, Huddleston JM, et al. Secular trends in hip fracture incidence and recurrence. Osteoporos Int. 2009; 20: 687-94.

[16] Griffith JF. Identifying osteoporotic vertebral fracture. Quant Imaging Med Surg. 2015; 5: 592-602.

[17] Cooper C, Atkinson EJ, O’Fallon WM, Melton LJ 3rd. Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985-1989. J Bone Miner Res. 1992; 7: 221-7.

[18] Melton LJ 3rd, Kallmes DF. Epidemiology of vertebral fractures: implications for vertebral augmentation. Acad Radiol. 2006; 13: 538-45.

[19] Nevitt MC, Ettinger B, Black DM, Stone K, Jamal SA, Ensrud K, et al. The association of radiographically detected vertebral fractures with back pain and function: a prospective study. Ann Intern Med. 1998; 128: 793-800.

[20] Delmas PD, van de Langerijt L, Watts NB, Eastell R, Genant H, Grauer A, et al.; IMPACT Study Group. Underdiagnosis of vertebral fractures is a worldwide problem: the IMPACT study. J Bone Miner Res. 2005; 20: 557-63.

[21] Melton LJ 3rd, Atkinson EJ, Cooper C, O’Fallon WM, Riggs BL. Vertebral fractures predict subsequent fractures. Osteoporos Int. 1999; 10: 214-21.

[22] Haentjens P, Johnell O, Kanis JA, Bouillon R, Cooper C, Lamraski G, et al. Network on Male Osteoporosis in Europe (NEMO). Evidence from data searches and life-table analyses for gender-related differences in absolute risk of hip fracture after Colles' or spine fracture: Colles’ fracture as an early and sensitive marker of skeletal fragility in white men. J Bone Miner Res. 2004; 19: 1933-44.

[23] Owen RA, Melton LJ 3rd, Johnson KA, Ilstrup DM, Riggs BL. Incidence of Colles’ fracture in a North American community. Am J Public Health. 1982; 72: 605-7.

[24] Ismail AA, Pye SR, Cockerill WC, Lunt M, Silman AJ, Reeve J, et al. Incidence of limb fracture across Europe: results from the European Prospective Osteoporosis Study (EPOS). Osteoporos Int. 2002; 13: 565-71.

[25] Zhu Z, Yu P, Wu Y, Wu Y, Tan Z, Ling J, et al. Sex Specific Global Burden of Osteoporosis in 204 Countries and Territories, from 1990 to 2030: An Age-Period-Cohort Modeling Study. J Nutr Health Aging. 2023; 27: 767-74.

[26] Kanis JA. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporos Int. 1994; 4: 368-81.

[27] Docaj A, Carriero A. Bone health: Quality versus quantity. J Pediatr Soc North Am. 2024; 7: 100054.

[28] Osteoporosis prevention, diagnosis, and therapy. NIH Consens Statement. 2000; 17: 1-45.

[29] Bone mass [Internet]. [cited 2025 Dec 31]. Available from: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bone-mass

[30] John A Kanis on behalf of the World Health Organization Scientific Group. Assessment of osteoporosis at the primary health care level. Sheffield (UK): WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School; 2007.

[31] Kanis JA, Melton LJ 3rd, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. 1994; 9: 1137-41.

[32] Cummings SR, Bates D, Black DM. Clinical use of bone densitometry: scientific review. JAMA. 2002; 288: 1889-97.

[33] Bouxsein ML. Technology insight: noninvasive assessment of bone strength in osteoporosis. Nat Clin Pract Rheumatol. 2008; 4: 310-8.

[34] Engelke K, Glüer CC. Quality and performance measures in bone densitometry: part 1: errors and diagnosis. Osteoporos Int. 2006; 17: 1283-92.

[35] Martins PC, Alves Junior CAS, Silva AM, Silva DAS. Phase angle and body composition: A scoping review. Clin Nutr ESPEN. 2023; 56: 237-50.

[36] Bhattacharya A, Watts NB, Gordon J, Shukla R, Waters T, Bartels S, et al. Bone quantity and quality of youths working on a farm-a pilot study. J Agromedicine. 2007; 12: 27-38.

[37] Alomari AH, Wille ML, Langton CM. Bone volume fraction and structural parameters for estimation of mechanical stiffness and failure load of human cancellous bone samples; in-vitro comparison of ultrasound transit time spectroscopy and X-ray μCT. Bone. 2018; 107: 145-53.

[38] Compston J. Bone quality: what is it and how is it measured? Arq Bras Endocrinol Metabol. 2006; 50: 579-85.

[39] Licata A. Bone density vs bone quality: what’s a clinician to do? Cleve Clin J Med. 2009; 76: 331-6.

[40] Brickley MB, Mays S. Metabolic disease. In: Ortner’s identification of pathological conditions in human skeletal remains. 2nd ed. Academic Press; 2019. pp. 531-66.

[41] Paschalis EP, Mendelsohn R, Boskey AL. Infrared assessment of bone quality: a review. Clin Orthop Relat Res. 2011; 469: 2170-8.

[42] Lloret MJ, Fusaro M, Jørgensen HS, Haarhaus M, Gifre L, Alfieri CM, et al. Evaluating Osteoporosis in Chronic Kidney Disease: Both Bone Quantity and Quality Matter. J Clin Med. 2024; 13: 1010.

[43] Sheu A, Diamond T. Bone mineral density: testing for osteoporosis. Aust Prescr. 2016; 39: 35-9.

[44] Amarnath SS, Kumar V, Das SL. Classification of Osteoporosis. Indian J Orthop. 2023; 57: 49-54.

[45] Indications for Bone Mineral Density (BMD) Testing [Internet]. [cited 2025 Aug 28]. Available from: https://iscd.org/official-positions-2023/

[46] Bianchi ML, Baim S, Bishop NJ, Gordon CM, Hans DB, Langman CB, et al. Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents. Pediatr Nephrol. 2010; 25: 37-47.

[47] Aibar-Almazán A, Voltes-Martínez A, Castellote-Caballero Y, Afanador-Restrepo DF, Carcelén-Fraile MDC, López-Ruiz E. Current Status of the Diagnosis and Management of Osteoporosis. Int J Mol Sci. 2022; 23: 9465.

[48] Lorentzon M, Cummings SR. Osteoporosis: the evolution of a diagnosis. J Intern Med. 2015; 277: 650-61.

[49] Ciancia S, van Rijn RR, Högler W, Appelman-Dijkstra NM, Boot AM, Sas TCJ, et al. Osteoporosis in children and adolescents: when to suspect and how to diagnose it. Eur J Pediatr. 2022; 181: 2549-61.

[50] Skowrońska-Jóźwiak E, Lorenc RS. Metabolic bone disease in children: etiology and treatment options. Treat Endocrinol. 2006; 5: 297-318.

[51] Testini V, Eusebi L, Tupputi U, Carpagnano FA, Bartelli F, Guglielmi G. Metabolic Bone Diseases in the Pediatric Population. Semin Musculoskelet Radiol. 2021; 25: 94-104.

[52] Lorenc RS. Idiopathic juvenile osteoporosis. Calcif Tissue Int. 2002; 70: 395-7.

[53] Rauch F, Travers R, Norman ME, Taylor A, Parfitt AM, Glorieux FH. The bone formation defect in idiopathic juvenile osteoporosis is surface-specific. Bone. 2002; 31: 85-9.

[54] Laine CM, Laine T. Diagnosis of Osteoporosis in Children and Adolescents. Eur Endocrinol. 2013; 9: 141-4.

[55] Christenson RH. Biochemical markers of bone metabolism: an overview. Clin Biochem. 1997; 30: 573-93.

[56] Rozenberg S, Bruyère O, Bergmann P, Cavalier E, Gielen E, Goemaere S, et al. How to manage osteoporosis before the age of 50. Maturitas. 2020; 138: 14-25.

[57] Boonen S, Kaufman JM, Goemaere S, Bouillon R, Vanderschueren D. The diagnosis and treatment of male osteoporosis: Defining, assessing, and preventing skeletal fragility in men. Eur J Intern Med. 2007; 18: 6-17.

[58] Vidal L, Vidal M, Cabrera S, Ortega E, Santiváñez V, Polo J, et al. Metabolismo mineral óseo durante la gestación y efectos sobre la masa ósea de la madre. An Fac Med. 2008; 69: 198-205.

[59] Scioscia MF, Vidal M, Sarli M, Guelman R, Danilowicz K, Mana D, et al. Severe Bone Microarchitecture Impairment in Women With Pregnancy and Lactation-Associated Osteoporosis. J Endocr Soc. 2021; 5:bvab031.

[60] Kovacs CS. Complex clinical encounter series: osteoporosis presenting during pregnancy and lactation: wait and reassess. J Bone Miner Res. 2024; 39: 197-201.

[61] Kovacs CS, Ralston SH. Presentation and management of osteoporosis presenting in association with pregnancy or lactation. Osteoporos Int. 2015; 26: 2223-41.

[62] Gashi A, Ismajli J, Berisha I, Elshani B, Rraci B, Berisha A. Osteoporosis during Pregnancy - Case Report and Review. Rheumatology (Bulgaria). 2021; 29: 85-90.

[63] Kalkwarf HJ. Lactation and maternal bone health. Adv Exp Med Biol. 2004; 554: 101-14.

[64] Thomas M, Weisman SM. Calcium supplementation during pregnancy and lactation: effects on the mother and the fetus. Am J Obstet Gynecol. 2006; 194: 937-45.

[65] Carsote M, Turturea MR, Valea A, Buescu C, Nistor C, Turturea IF. Bridging the Gap: Pregnancy-And Lactation-Associated Osteoporosis. Diagnostics (Basel). 2023; 13: 1615.

[66] Riggs BL. Overview of osteoporosis. West J Med. 1991; 154: 63-77.

[67] Johnston CB, Dagar M. Osteoporosis in Older Adults. Med Clin North Am. 2020; 104: 873-84.

[68] Ebeling PR, Nguyen HH, Aleksova J, Vincent AJ, Wong P, Milat F. Secondary Osteoporosis. Endocr Rev. 2022; 43: 240-313.

[69] Panday K, Gona A, Humphrey MB. Medication-induced osteoporosis: screening and treatment strategies. Ther Adv Musculoskelet Dis. 2014; 6: 185-202.

[70] Ganesan K, Jandu JS, Anastasopoulou C, Ahsun S, Roane D. Secondary Osteoporosis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025.

[71] Lei S, Zhang X, Song L, Wen J, Zhang Z, Tian J, et al. Expert consensus on vitamin D in osteoporosis. Ann Jt. 2025; 10: 1.

[72] Sabri SA, Chavarria JC, Ackert-Bicknell C, Swanson C, Burger E. Osteoporosis: An Update on Screening, Diagnosis, Evaluation, and Treatment. Orthopedics. 2023; 46: e20-6.

[73] Hofbauer LC, Hamann C, Ebeling PR. Approach to the patient with secondary osteoporosis. Eur J Endocrinol. 2010; 162: 1009-20.

[74] Bianchi ML, Bishop NJ, Guañabens N, Hofmann C, Jakob F, Roux C, et al.; Rare Bone Disease Action Group of the European Calcified Tissue Society. Hypophosphatasia in adolescents and adults: overview of diagnosis and treatment. Osteoporos Int. 2020; 31: 1445-60.

[75] Choida V, Bubbear JS. Update on the management of hypophosphatasia. Ther Adv Musculoskelet Dis. 2019; 11: 1759720X19863997.

[76] Seefried L, Alzahrani A, Arango Sancho P, Bacchetta J, Crowley R, Emma F, et al. XLH Matters 2022: Insights and recommendations to improve outcomes for people living with X-linked hypophosphataemia (XLH). Orphanet J Rare Dis. 2023; 18: 333.

[77] Forlino A, Marini JC. Osteogenesis imperfecta. Lancet. 2016; 387: 1657-71.

[78] Charoenngam N, Rittiphairoj T, Ponvilawan B, Jaroenlapnopparat A, Waitayangkoon P, Suppakitjanusant P, et al. Bone Fragility in Hereditary Connective Tissue Disorders: A Systematic Review and Meta-Analysis. Endocr Pract. 2023; 29: 589-600.

[79] Mazziotti G, Dordoni C, Doga M, Galderisi F, Venturini M, Calzavara-Pinton P, et al. High prevalence of radiological vertebral fractures in adult patients with Ehlers-Danlos syndrome. Bone. 2016; 84: 88-92.

[80] Eller-Vainicher C, Bassotti A, Imeraj A, Cairoli E, Ulivieri FM, Cortini F, et al. Bone involvement in adult patients affected with Ehlers-Danlos syndrome. Osteoporos Int. 2016; 27: 2525-31.

[81] Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes-a meta-analysis. Osteoporos Int. 2007; 18: 427-44.

[82] Bolanowski M, Halupczok J, Jawiarczyk-Przybyłowska A. Pituitary disorders and osteoporosis. Int J Endocrinol. 2015; 2015: 206853.

[83] Wüster C, Abs R, Bengtsson BA, Bennmarker H, Feldt-Rasmussen U, Hernberg-Ståhl E, et al.; KIMS Study Group and the KIMS International Board. Pharmacia & Upjohn International Metabolic Database. The influence of growth hormone deficiency, growth hormone replacement therapy, and other aspects of hypopituitarism on fracture rate and bone mineral density. J Bone Miner Res. 2001; 16: 398-405.

[84] Cohen A, Shane E. Evaluation and management of the premenopausal woman with low BMD. Curr Osteoporos Rep. 2013; 11: 276-85.

[85] Misra M. Effects of hypogonadism on bone metabolism in female adolescents and young adults. Nat Rev Endocrinol. 2012; 8: 395-404.

[86] WHO Guidelines on Hepatitis B and C Testing. Geneva: World Health Organization; 2017.

[87] Al Nofal AA, Altayar O, BenKhadra K, Qasim Agha OQ, Asi N, Nabhan M, et al. Bone turnover markers in Paget’s disease of the bone: A Systematic review and meta-analysis. Osteoporos Int. 2015; 26: 1875-91.

[88] Vidal LF, Vidal M, Lane NE, Keen R, Alba R. Doses and schemes for correcting vitamin D deficiency: an update. Food Nutr J. 2024; 9: 290.

[89] Vidal M, Lane NE. The importance of vitamin D. ROM. 2020; 5: 1-9.

[90] Tuckey RC, Cheng CYS, Slominski AT. The serum vitamin D metabolome: What we know and what is still to discover. J Steroid Biochem Mol Biol. 2019; 186: 4-21.

[91] Makris K, Sempos C, Cavalier E. The measurement of vitamin D metabolites part II-the measurement of the various vitamin D metabolites. Hormones (Athens). 2020; 19: 97-107.

[92] Holick MF. Vitamin D: A millenium perspective. J Cell Biochem. 2003; 88: 296-307.

[93] Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999; 69: 842-56.

[94] Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011; 96: 1911-30.

[95] Chevalley T, Brandi ML, Cashman KD, Cavalier E, Harvey NC, Maggi S, et al. Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group. Aging Clin Exp Res. 2022; 34: 2603-23.

[96] Bertoldo F, Cianferotti L, Di Monaco M, Falchetti A, Fassio A, Gatti D, et al. Definition, Assessment, and Management of Vitamin D Inadequacy: Suggestions, Recommendations, and Warnings from the Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS). Nutrients. 2022; 14: 4148.

[97] Al Saleh Y, Beshyah SA, Hussein W, Almadani A, Hassoun A, Al Mamari A, et al. Diagnosis and management of vitamin D deficiency in the Gulf Cooperative Council (GCC) countries: an expert consensus summary statement from the GCC vitamin D advisory board. Arch Osteoporos. 2020; 15: 35.

[98] Camacho PM, Petak SM, Binkley N, Diab DL, Eldeiry LS, Farooki A, et al. American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis-2020 update. Endocr Pract. 2020; 26: 1-46.

[99] Casado E, Quesada JM, Naves M, Peris P, Jódar E, Giner M, et al. Recomendaciones de la SEIOMM en la prevención y tratamiento del déficit de vitamina D. Rev Osteoporos Metab Miner. 2021; 13: 84-97.

[100] Pludowski P, Takacs I, Boyanov M, Belaya Z, Diaconu CC, Mokhort T, et al. Clinical Practice in the Prevention, Diagnosis and Treatment of Vitamin D Deficiency: A Central and Eastern European Expert Consensus Statement. Nutrients. 2022; 14: 1483.

[101] Gregson CL, Armstrong DJ, Bowden J, Cooper C, Edwards J, Gittoes NJL, et al. UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos. 2022; 17: 58.

[102] Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, et al. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporos Int. 2014; 25: 2359-81.

[103] Souberbielle JC, Cormier C, Cavalier E, Breuil V, Debiais F, Fardellone P, et al.; au nom du Groupe de recherche et d’information sur les ostéoporoses, (GRIO). Vitamin D Supplementation in France in patients with or at risk for osteoporosis: Recent data and new practices. Joint Bone Spine. 2020; 87: 25-9.

[104] Khundmiri SJ, Murray RD, Lederer E. PTH and Vitamin D. Compr Physiol. 2016; 6: 561-601.

[105] Pepe J, Colangelo L, Pilotto R, De Martino V, Ferrara C, Scillitani A, et al. Short-Term Effects of Escalating Doses of Cholecalciferol on FGF23 and 24,25(OH)₂ Vitamin D Levels: A Preliminary Investigation. Nutrients. 2024; 16: 3600.

[106] Jeon SM, Shin EA. Exploring vitamin D metabolism and function in cancer. Exp Mol Med. 2018; 50: 1-14.

[107] Collins L, Boehm E, Luxford C, Clifton-Bligh R, Grill V. Hypervitaminosis D Secondary to a CYP24A1 Loss-of-Function Mutation: An Unusual Cause of Hypercalcemia in Two Siblings. JBMR Plus. 2023; 7: e10788.

[108] Meyer MB, Pike JW. Mechanistic homeostasis of vitamin D metabolism in the kidney through reciprocal modulation of Cyp27b1 and Cyp24a1 expression. J Steroid Biochem Mol Biol. 2020; 196: 105500.

[109] Vidal M, Lane NE. Vitamin D and Its Role in Rheumatic Diseases. Metabolites. 2025; 15: 259.

[110] Giustina A, Bouillon R, Dawson-Hughes B, Ebeling PR, Lazaretti-Castro M, Lips P, et al. Vitamin D in the older population: a consensus statement. Endocrine. 2023; 79: 31-44.

[111] Calcium: Fact Sheet for Health Professionals [Internet]. [cited 2025 Aug 28]. Available from: https://ods.od.nih.gov/factsheets/Calcium-HealthProfessional/

[112] Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. The National Academies Collection: Reports funded by National Institutes of Health. In: Ross AC, Taylor CL, Yaktine AL, Del Valle HB, editors. Dietary Reference Intakes for Calcium and Vitamin D. Washington (DC): National Academies Press (US); 2011.

[113] Rizzoli R, Biver E, Brennan-Speranza TC. Nutritional intake and bone health. Lancet Diabetes Endocrinol. 2021; 9: 606-21.

[114] Heaney RP, Weaver CM, Recker RR. Calcium absorbability from spinach. Am J Clin Nutr. 1988; 47: 707-9.

[115] Weaver CM, Alexander DD, Boushey CJ, Dawson-Hughes B, Lappe JM, LeBoff MS, et al. Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the National Osteoporosis Foundation. Osteoporos Int. 2016; 27: 367-76.

[116] Iuliano S, Poon S, Robbins J, Bui M, Wang X, De Groot L, et al. Effect of dietary sources of calcium and protein on hip fractures and falls in older adults in residential care: cluster randomised controlled trial. BMJ. 2021; 375: n2364.

[117] Voulgaridou G, Papadopoulou SK, Detopoulou P, Tsoumana D, Giaginis C, Kondyli FS, et al. Vitamin D and Calcium in Osteoporosis, and the Role of Bone Turnover Markers: A Narrative Review of Recent Data from RCTs. Diseases. 2023; 11: 29.

[118] Yao P, Bennett D, Mafham M, Lin X, Chen Z, Armitage J, et al. Vitamin D and Calcium for the Prevention of Fracture: A Systematic Review and Meta-analysis. JAMA Netw Open. 2019; 2: e1917789.

[119] Manoj P, Derwin R, George S. What is the impact of daily oral supplementation of vitamin D3 (cholecalciferol) plus calcium on the incidence of hip fracture in older people? A systematic review and meta-analysis. Int J Older People Nurs. 2023; 18: e12492.

[120] Tucker KL. Vegetarian diets and bone status. Am J Clin Nutr. 2014; 100 Suppl 1: 329S-35S.

[121] Tong TYN, Appleby PN, Armstrong MEG, Fensom GK, Knuppel A, Papier K, et al. Vegetarian and vegan diets and risks of total and site-specific fractures: results from the prospective EPIC-Oxford study. BMC Med. 2020; 18: 353.

[122] Ho-Pham LT, Nguyen ND, Nguyen TV. Effect of vegetarian diets on bone mineral density: a Bayesian meta-analysis. Am J Clin Nutr. 2009; 90: 943-50.

[123] Mangels AR. Bone nutrients for vegetarians. Am J Clin Nutr. 2014; 100 Suppl 1: 469S-75S.

[124] Falchetti A, Cavati G, Valenti R, Mingiano C, Cosso R, Gennari L, et al. The effects of vegetarian diets on bone health: A literature review. Front Endocrinol (Lausanne). 2022; 13: 899375.

[125] Yuan S, Wan ZH, Cheng SL, Michaëlsson K, Larsson SC. Insulin-like Growth Factor-1, Bone Mineral Density, and Fracture: A Mendelian Randomization Study. J Clin Endocrinol Metab. 2021; 106: e1552-8.

[126] Herrmann W, Schorr H, Obeid R, Geisel J. Vitamin B-12 status, particularly holotranscobalamin II and methylmalonic acid concentrations, and hyperhomocysteinemia in vegetarians. Am J Clin Nutr. 2003; 78: 131-6.

[127] Dhonukshe-Rutten RA, Lips M, de Jong N, Chin A Paw MJ, Hiddink GJ, van Dusseldorp M, et al. Vitamin B-12 status is associated with bone mineral content and bone mineral density in frail elderly women but not in men. J Nutr. 2003; 133: 801-7.

[128] Merlotti D, Mingiano C, Valenti R, Cavati G, Calabrese M, Pirrotta F, et al. Bone Fragility in Gastrointestinal Disorders. Int J Mol Sci. 2022; 23: 2713.

[129] Hao L, Mu S, Yin J, Liu J. A meta-analysis of the risk of osteoporotic fractures in inflammatory bowel disease. Adv Clin Exp Med. 2024; 33: 327-33.

[130] Szafors P, Che H, Barnetche T, Morel J, Gaujoux-Viala C, Combe B, et al. Risk of fracture and low bone mineral density in adults with inflammatory bowel diseases. A systematic literature review with meta-analysis. Osteoporos Int. 2018; 29: 2389-97.

[131] Laakso S, Valta H, Verkasalo M, Toiviainen-Salo S, Viljakainen H, Mäkitie O. Impaired bone health in inflammatory bowel disease: a case-control study in 80 pediatric patients. Calcif Tissue Int. 2012; 91: 121-30.

[132] Zacay G, Weintraub I, Regev R, Modan-Moses D, Levy-Shraga Y. Fracture risk among children and adolescents with celiac disease: a nationwide cohort study. Pediatr Res. 2024; 95: 386-92.

[133] Hansen S, Schwarz P, Rumessen J, Linneberg A, Kårhus LL. Osteoporosis and bone fractures in patients with celiac disease: A nationwide cohort study. Bone. 2023; 177: 116913.

[134] Fedewa MV, Bentley JL, Higgins S, Kindler JM, Esco MR, MacDonald HV. Celiac Disease and Bone Health in Children and Adolescents: A Systematic Review and Meta-Analysis. J Clin Densitom. 2020; 23: 200-11.

[135] Heikkilä K, Pearce J, Mäki M, Kaukinen K. Celiac disease and bone fractures: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2015; 100: 25-34.

[136] Lionetti E, Catassi C. The Role of Environmental Factors in the Development of Celiac Disease: What Is New? Diseases. 2015; 3: 282-93.

[137] Oliveira DDC, da Silva DCG, Kawano MM, de Castro CT, Pereira M. Effect of a gluten-free diet on bone mineral density in children and adolescents with celiac disease: Systematic review and meta-analysis. Crit Rev Food Sci Nutr. 2024; 64: 5192-202.

[138] Yin Y, Liang H, Wei N, Zheng Z. Prevalence of chronic atrophic gastritis worldwide from 2010 to 2020: an updated systematic review and meta-analysis. Ann Palliat Med. 2022; 11: 3697-703.

[139] Kuang W, Xu J, Xu F, Huang W, Majid M, Shi H, et al. Current study of pathogenetic mechanisms and therapeutics of chronic atrophic gastritis: a comprehensive review. Front Cell Dev Biol. 2024; 12: 1513426.

[140] Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev. 2006; 19: 449-90.

[141] Lee YC, Dore MP, Graham DY. Diagnosis and Treatment of Helicobacter pylori Infection. Annu Rev Med. 2022; 73: 183-95.

[142] Oh DJ, Nam JH, Lee HS, Moon YR, Lim YJ. The combined use of anti-peptic agents is associated with an increased risk of osteoporotic fracture: a nationwide case-control study. Korean J Intern Med. 2024; 39: 228-37.

[143] Guañabens N, Parés A. Osteoporosis in chronic liver disease. Liver Int. 2018; 38: 776-85.

[144] Handzlik-Orlik G, Holecki M, Wilczyński K, Duława J. Osteoporosis in liver disease: pathogenesis and management. Ther Adv Endocrinol Metab. 2016; 7: 128-35.

[145] Yang YJ, Kim DJ. An Overview of the Molecular Mechanisms Contributing to Musculoskeletal Disorders in Chronic Liver Disease: Osteoporosis, Sarcopenia, and Osteoporotic Sarcopenia. Int J Mol Sci. 2021; 22: 2604.

[146] Bang CS, Shin IS, Lee SW, Kim JB, Baik GH, Suk KT, et al. Osteoporosis and bone fractures in alcoholic liver disease: a meta-analysis. World J Gastroenterol. 2015; 21: 4038-47.

[147] Pan B, Cai J, Zhao P, Liu J, Fu S, Jing G, et al. Relationship between prevalence and risk of osteoporosis or osteoporotic fracture with non-alcoholic fatty liver disease: A systematic review and meta-analysis. Osteoporos Int. 2022; 33: 2275-86.

[148] Lupoli R, Di Minno A, Spadarella G, Ambrosino P, Panico A, Tarantino L, et al. The risk of osteoporosis in patients with liver cirrhosis: a meta-analysis of literature studies. Clin Endocrinol (Oxf). 2016; 84: 30-8.

[149] Shirinezhad A, Eshlaghi FM, Salabat D, Azarboo A, Ardakani ZF, Esmaeili S, et al. Prevalent osteoporosis and fracture risk in patients with hepatic cirrhosis: a systematic review and meta-analysis. BMC Gastroenterol. 2025; 25: 115.

[150] Terrault NA, Francoz C, Berenguer M, Charlton M, Heimbach J. Liver Transplantation 2023: Status Report, Current and Future Challenges. Clin Gastroenterol Hepatol. 2023; 21: 2150-66.

[151] Trebicka J, Sundaram V, Moreau R, Jalan R, Arroyo V. Liver Transplantation for Acute-on-Chronic Liver Failure: Science or Fiction? Liver Transpl. 2020; 26: 906-15.

[152] Lim WH, Ng CH, Ow ZGW, Ho OTW, Tay PWL, Wong KL, et al. A systematic review and meta-analysis on the incidence of osteoporosis and fractures after liver transplant. Transpl Int. 2021; 34: 1032-43.

[153] Evenepoel P, Cunningham J, Ferrari S, Haarhaus M, Javaid MK, Lafage-Proust MH, et al.; European Renal Osteodystrophy (EUROD) workgroup, an initiative of the CKD-MBD working group of the ERA-EDTA, and the committee of Scientific Advisors and National Societies of the IOF. European Consensus Statement on the diagnosis and management of osteoporosis in chronic kidney disease stages G4-G5D. Nephrol Dial Transplant. 2021; 36: 42-59.

[154] Hsu CY, Chen LR, Chen KH. Osteoporosis in Patients with Chronic Kidney Diseases: A Systemic Review. Int J Mol Sci. 2020; 21: 6846.

[155] Goto NA, Weststrate ACG, Oosterlaan FM, Verhaar MC, Willems HC, Emmelot-Vonk MH, et al. The association between chronic kidney disease, falls, and fractures: a systematic review and meta-analysis. Osteoporos Int. 2020; 31: 13-29.

[156] Nickolas TL, Leonard MB, Shane E. Chronic kidney disease and bone fracture: a growing concern. Kidney Int. 2008; 74: 721-31.

[157] Nickolas TL, McMahon DJ, Shane E. Relationship between moderate to severe kidney disease and hip fracture in the United States. J Am Soc Nephrol. 2006; 17: 3223-32.

[158] Alem AM, Sherrard DJ, Gillen DL, Weiss NS, Beresford SA, Heckbert SR, et al. Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int. 2000; 58: 396-9.

[159] Vilaca T, Salam S, Schini M, Harnan S, Sutton A, Poku E, et al. Risks of Hip and Nonvertebral Fractures in Patients With CKD G3a-G5D: A Systematic Review and Meta-analysis. Am J Kidney Dis. 2020; 76: 521-32.

[160] Gute L, Zimbudzi E. Interventions to reduce falls among dialysis patients: a systematic review. BMC Nephrol. 2023; 24: 382.

[161] Tang J, Wang B, Yuan Q, Li X. Prevalence and risk factors of falls in people on hemodialysis: a systematic review and meta-analysis. Ren Fail. 2025; 47: 2485375.

[162] Liu X, Liu Z, Niu Y, Zhang K, Zhang X, Yu C. The Relationship Between Fracture and Mortality in a Chinese Maintenance Hemodialysis Patients Cohort. J Multidiscip Healthc. 2024; 17: 2031-8.

[163] Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006; 12: 6243s-9s.

[164] Coleman RE. Skeletal complications of malignancy. Cancer. 1997; 80: 1588-94.

[165] Zajączkowska R, Kocot-Kępska M, Leppert W, Wordliczek J. Bone Pain in Cancer Patients: Mechanisms and Current Treatment. Int J Mol Sci. 2019; 20: 6047.

[166] Clézardin P. Pathophysiology of bone metastases from solid malignancies. Joint Bone Spine. 2017; 84: 677-84.

[167] Weilbaecher KN, Guise TA, McCauley LK. Cancer to bone: a fatal attraction. Nat Rev Cancer. 2011; 11: 411-25.

[168] Macedo F, Ladeira K, Pinho F, Saraiva N, Bonito N, Pinto L, et al. Bone Metastases: An Overview. Oncol Rev. 2017; 11: 321.

[169] Ryan C, Stoltzfus KC, Horn S, Chen H, Louie AV, Lehrer EJ, et al. Epidemiology of bone metastases. Bone. 2022; 158: 115783.

[170] Kuchuk M, Kuchuk I, Sabri E, Hutton B, Clemons M, Wheatley-Price P. The incidence and clinical impact of bone metastases in non-small cell lung cancer. Lung Cancer. 2015; 89: 197-202.

[171] Kimura T. Multidisciplinary Approach for Bone Metastasis: A Review. Cancers (Basel). 2018; 10: 156.

[172] Silbermann R, Roodman GD. Myeloma bone disease: Pathophysiology and management. J Bone Oncol. 2013; 2: 59-69.

[173] Kristinsson SY, Minter AR, Korde N, Tan E, Landgren O. Bone disease in multiple myeloma and precursor disease: novel diagnostic approaches and implications on clinical management. Expert Rev Mol Diagn. 2011; 11: 593-603.

[174] Keller ET, Brown J. Prostate cancer bone metastases promote both osteolytic and osteoblastic activity. J Cell Biochem. 2004; 91: 718-29.

[175] Corey E, Brown LG, Kiefer JA, Quinn JE, Pitts TE, Blair JM, et al. Osteoprotegerin in prostate cancer bone metastasis. Cancer Res. 2005; 65: 1710-8.

[176] Ban J, Fock V, Aryee DNT, Kovar H. Mechanisms, Diagnosis and Treatment of Bone Metastases. Cells. 2021; 10: 2944.

[177] Kurokawa R, Kato S, Koyama H, Ishida M, Kurokawa M, Kuroda R, et al. Osteolytic or mixed bone metastasis is not uncommon in patients with high-risk prostate cancer. Eur J Radiol. 2022; 157: 110595.

[178] Tsuzuki S, Park SH, Eber MR, Peters CM, Shiozawa Y. Skeletal complications in cancer patients with bone metastases. Int J Urol. 2016; 23: 825-32.

[179] Rosner MH, Dalkin AC. Onco-nephrology: the pathophysiology and treatment of malignancy-associated hypercalcemia. Clin J Am Soc Nephrol. 2012; 7: 1722-9.

[180] Cirstoiu C, Cretu B, Iordache S, Popa M, Serban B, Cursaru A. Surgical management options for long-bone metastasis. EFORT Open Rev. 2022; 7: 206-13.

[181] Robson P. Metastatic spinal cord compression: a rare but important complication of cancer. Clin Med (Lond). 2014; 14: 542-5.

[182] Kenan S, Mechanick JI. Skeletal Metastases. In: Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

[183] Messina OD, Vidal M, Adami G, Vidal LF, Clark P, Torres JAM, et al. Chronic arthritides and bone structure: focus on rheumatoid arthritis-an update. Aging Clin Exp Res. 2023; 35: 1405-16.

[184] Adami G, Fassio A, Rossini M, Caimmi C, Giollo A, Orsolini G, et al. Osteoporosis in Rheumatic Diseases. Int J Mol Sci. 2019; 20: 5867.

[185] Baum R, Gravallese EM. Impact of inflammation on the osteoblast in rheumatic diseases. Curr Osteoporos Rep. 2014; 12: 9-16.

[186] Weivoda MM, Ruan M, Hachfeld CM, Pederson L, Howe A, Davey RA, et al. Wnt Signaling Inhibits Osteoclast Differentiation by Activating Canonical and Noncanonical cAMP/PKA Pathways. J Bone Miner Res. 2016; 31: 65-75.

[187] Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003; 349: 2483-94.

[188] Ma Y, Zhang X, Wang M, Xia Q, Yang J, Wu M, et al. The serum level of Dickkopf-1 in patients with rheumatoid arthritis: A systematic review and meta-analysis. Int Immunopharmacol. 2018; 59: 227-32.

[189] Rossini M, Viapiana O, Adami S, Fracassi E, Idolazzi L, Dartizio C, et al. In patients with rheumatoid arthritis, Dickkopf-1 serum levels are correlated with parathyroid hormone, bone erosions and bone mineral density. Clin Exp Rheumatol. 2015; 33: 77-83.

[190] Uderhardt S, Diarra D, Katzenbeisser J, David JP, Zwerina J, Richards W, et al. Blockade of Dickkopf (DKK)-1 induces fusion of sacroiliac joints. Ann Rheum Dis. 2010; 69: 592-7.

[191] Allan LM, Ballard CG, Rowan EN, Kenny RA. Incidence and prediction of falls in dementia: a prospective study in older people. PLoS One. 2009; 4: e5521.

[192] Härlein J, Dassen T, Halfens RJ, Heinze C. Fall risk factors in older people with dementia or cognitive impairment: a systematic review. J Adv Nurs. 2009; 65: 922-33.

[193] Schini M, Bhatia P, Shreef H, Johansson H, Harvey NC, Lorentzon M, et al. Increased fracture risk in Parkinson’s disease - An exploration of mechanisms and consequences for fracture prediction with FRAX. Bone. 2023; 168: 116651.

[194] Xie C, Wang C, Luo H. Increased risk of osteoporosis in patients with cognitive impairment: a systematic review and meta-analysis. BMC Geriatr. 2023; 23: 797.

[195] Jeon JH, Park JH, Oh C, Chung JK, Song JY, Kim S, et al. Dementia is Associated with an Increased Risk of Hip Fractures: A Nationwide Analysis in Korea. J Clin Neurol. 2019; 15: 243-9.

[196] Matsumoto S, Hosoi T, Yakabe M, Fujimori K, Tamaki J, Nakatoh S, et al. Early-onset dementia and risk of hip fracture and major osteoporotic fractures. Alzheimers Dement. 2024; 20: 3388-96.

[197] Wang HK, Hung CM, Lin SH, Tai YC, Lu K, Liliang PC, et al. Increased risk of hip fractures in patients with dementia: a nationwide population-based study. BMC Neurol. 2014; 14: 175.

[198] Singh I, Duric D, Motoc A, Edwards C, Anwar A. Relationship of Prevalent Fragility Fracture in Dementia Patients: Three Years Follow up Study. Geriatrics (Basel). 2020; 5: 99.

[199] Malochet-Guinamand S, Durif F, Thomas T. Parkinson’s disease: A risk factor for osteoporosis. Joint Bone Spine. 2015; 82: 406-10.

[200] Pouwels S, Bazelier MT, de Boer A, Weber WE, Neef C, Cooper C, et al. Risk of fracture in patients with Parkinson’s disease. Osteoporos Int. 2013; 24: 2283-90.

[201] Huang YF, Cherng YG, Hsu SP, Yeh CC, Chou YC, Wu CH, et al. Risk and adverse outcomes of fractures in patients with Parkinson’s disease: two nationwide studies. Osteoporos Int. 2015; 26: 1723-32.

[202] Fhon JRS, Silva ARF, Lima EFC, Santos Neto APD, Henao-Castaño ÁM, Fajardo-Ramos E, et al. Association between Sarcopenia, Falls, and Cognitive Impairment in Older People: A Systematic Review with Meta-Analysis. Int J Environ Res Public Health. 2023; 20: 4156.

[203] Curtis EM, Miguel M, McEvoy C, Ticinesi A, Torre C, Al-Daghri N, et al. Impact of dementia and mild cognitive impairment on bone health in older people. Aging Clin Exp Res. 2024; 37: 5.

[204] van den Bos F, Speelman AD, Samson M, Munneke M, Bloem BR, Verhaar HJ. Parkinson’s disease and osteoporosis. Age Ageing. 2013; 42: 156-62.

[205] Vaserman N. Parkinson’s disease and osteoporosis. Joint Bone Spine. 2005; 72: 484-8.

[206] Liu B, Chen G, Yu Z, Ji C, Liang T, He J, et al. Bone Mineral Density and Related Scores in Parkinson’s Disease: A Systematic Review and Meta-Analysis. World Neurosurg. 2021; 146: e1202-18.

[207] Masnoon N, Shakib S, Kalisch-Ellett L, Caughey GE. What is polypharmacy? A systematic review of definitions. BMC Geriatr. 2017; 17: 230.

[208] Gagnon ME, Talbot D, Tremblay F, Desforges K, Sirois C. Polypharmacy and risk of fractures in older adults: A systematic review. J Evid Based Med. 2024; 17: 145-71.

[209] Park HY, Kim S, Sohn HS, Kwon JW. The Association between Polypharmacy and Hip Fracture in Osteoporotic Women: A Nested Case-Control Study in South Korea. Clin Drug Investig. 2019; 39: 63-71.

[210] Komorita Y, Ohkuma T, Iwase M, Fujii H, Oku Y, Higashi T, et al. Polypharmacy and bone fracture risk in patients with type 2 diabetes: The Fukuoka Diabetes Registry. Diabetes Res Clin Pract. 2021; 181: 109097.

[211] Wakasugi M, Yokoseki A, Wada M, Momotsu T, Sato K, Kawashima H, et al. Polypharmacy, chronic kidney disease, and incident fragility fracture: a prospective cohort study. J Bone Miner Metab. 2022; 40: 157-66.

[212] Kose E, Wakabayashi H, Yasuno N. Polypharmacy and Malnutrition Management of Elderly Perioperative Patients with Cancer: A Systematic Review. Nutrients. 2021; 13: 1961.

[213] Lai SW, Liao KF, Liao CC, Muo CH, Liu CS, Sung FC. Polypharmacy correlates with increased risk for hip fracture in the elderly: a population-based study. Medicine (Baltimore). 2010; 89: 295-9.

[214] Härstedt M, Rogmark C, Sutton R, Melander O, Fedorowski A. Polypharmacy and adverse outcomes after hip fracture surgery. J Orthop Surg Res. 2016; 11: 151.

[215] Watts NB. Fundamentals and pitfalls of bone densitometry using dual-energy X-ray absorptiometry (DXA). Osteoporos Int. 2004; 15: 847-54.

[216] Krueger D, Shives E, Siglinsky E, Libber J, Buehring B, Hansen KE, et al. DXA Errors Are Common and Reduced by Use of a Reporting Template. J Clin Densitom. 2019; 22: 115-24.

[217] Martineau P, Morgan SL, Leslie WD. Bone Mineral Densitometry Reporting: Pearls and Pitfalls. Can Assoc Radiol J. 2021; 72: 490-504.

[218] Lewiecki EM, Binkley N, Morgan SL, Shuhart CR, Camargos BM, Carey JJ, et al.; International Society for Clinical Densitometry. Best Practices for Dual-Energy X-ray Absorptiometry Measurement and Reporting: International Society for Clinical Densitometry Guidance. J Clin Densitom. 2016; 19: 127-40.

[219] Tuna F, Yavuz S, Demirbağ Kabayel DD, Sarıkaya A. Effects of clinical reanalysis in dual energy X-ray absorptiometry reports. Turk J Phys Med Rehabil. 2017; 63: 201-6.

[220] Qutbi M, Soltanshahi M, Shiravand Y, Gorzi SK, Shafiei B, Asli IN. Technical and patient-related sources of error and artifacts in bone mineral densitometry using dual-energy X-ray absorptiometry: A pictorial review. Indian J Radiol Imaging. 2020; 30: 362-71.

[221] Morgan SL, Prater GL. Quality in dual-energy X-ray absorptiometry scans. Bone. 2017; 104: 13-28.

[222] Krugh M, Langaker MD. Dual-Energy X-Ray Absorptiometry. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025.

[223] Lewiecki EM, Binkley N, Petak SM. DXA quality matters. J Clin Densitom. 2006; 9: 388-92.

[224] Schnatz PF, Marakovits KA, Dubois M, O’Sullivan DM. Osteoporosis screening and treatment guidelines: are they being followed? Menopause. 2011; 18: 1072-8.