2 Osteoporosis

Suggested citation:  Endocrine Society. Endocrine Facts and Figures: Bone and Mineral. First Edition. 2016.

Osteoporosis is a progressive disorder of bone, defined as a condition resulting in an increased risk of skeletal fractures due to a reduction in bone mass and deterioration of skeletal microstruture.27 It is characterized by low bone mass, microstructural deterioration, and porous bone, which collectively are associated with higher fracture risk.4 Although osteoporosis has a higher overall prevalence in women, it is also a concern in men. Beyond aging and the menopause, there are other well-defined conditions that lead to bone loss (see discussions in section 3).28

2.1 PREVALENCE AND INCIDENCE

The National Osteoporosis Foundation reported an overall 10.3% prevalence of osteoporosis in American adults aged 50 years or older, based on bone mineral density (BMD) at the femoral neck and lumbar spine.29 In 2010, this translated to 10.2 million individuals. An additional 43.4 million Americans (prevalence 43.9%) in the same age group were estimated to have low bone mass (osteopenia).29 Altogether, osteoporosis is thought to cause an estimated 2 million fractures each year in the US.

In 2013, it was reported that osteoporosis affects 8 million US women.30 As osteoporosis can manifest as fractures occurring at multiple skeletal sites, the incidence of fractures is a barometer of overall prevalence. Table 6 shows the rate of incident fractures among US men and women. Overall, the lifetime risk of wrist, hip, or vertebral fracture was estimated to be 30-40% in developed countries, nearly the same risk as that for coronary heart  disease.1

Table 6. Incidence of fractures among men and women in the United States, 2005.
  Women Men
Age 50-64 years 372,180 234,499
65-74 years 298,938 130,250
75-84 years 445,937 129,882
≥ 85 years 338,788 100,222
Race/Ethnicity Caucasian 1,290,168 477,852
African American 58,923 48,525
Hispanic 61,668 41,134
Other 45,085 27,341
Total 1,455,843 594,852

Source: Burge et al. 20074

Data from NHANES III suggest that more than half of Americans age ≥ 50 years have osteoporosis or low bone mass at the femur neck or lumbar spine (Table 7).

Table 7. Skeletal status (femur neck or lumbar spine) of United States adults age ≥ 50 years.
Status Percentage
Normal 48%
Low bone mass (osteopenia) 49%
Osteoporosis 9%
Note: Percentages do not sum to 100% due to double counting of osteoporosis patients with disease at other sites.

Source: Looker et al. 19973

As mentioned above, about 75-80% of Americans with osteoporosis are women,% an association with reduced fractures and increased BMD, and recommended assessing patients with T-scores > -2.5 at the end of treatment for possible drug discontinuation with continued monitoring.58 A retrospective analysis of a US claims database that included 57,913 postmenopausal women age ≥ 55 years who filled one or more pharmacy claims for a bisphosphonate or non-bisphosphonate (e.g., raloxifene, calcitonin, or teriparatide) found that only 23,430 (40.5%) subjects were compliant. Noncompliant participants had a 20% greater risk of fracture and 13% higher medical costs.59 These results confirm and expand findings from an earlier and similar study in Canada that reported a 16% lower osteoporosis-related fracture rate among medication-compliant women age >50 years.6020and most are postmenopausal.31 At age 50 years, the lifetime risk of developing osteoporosis-related fractures is about 40% for Caucasian women and 13% for Caucasian men.32 By age 60 years, approximately 50% of US women have osteopenia (low bone mass) or osteoporosis.3 In addition, it is estimated that more than 20% of postmenopausal women exhibit prevalent vertebral fractures.33 Table 8 summarizes the prevalence of low BMD at the femoral neck in postmenopausal US women by race/ethnicity.

Table 8. Low bone mineral density at the femoral neck in postmenopausal United States women.
Race/Ethnicity Prevalence
Caucasian 21%
African American 10%
Mexican American 16%

Source: Looker et al. 19973

Estimates suggest that by 2025 the incidence of osteoporosis will rise by 50%, and over 87% of this increase will occur among those age 65-74 years.4 Other researchers have highlighted the negative outcomes associated with recurrent fractures and observed that first and repeat fractures increased by 60-70% per decade of age in a study population age 50-90 years; in this group, repeat fractures were more common among patients with low BMD.34

2.2 DEMOGRAPHIC DIFFERENCES

Data presented in Table 2 suggest that increasing age is a risk factor for the increased cost of osteoporosis. In addition, Table 7, which includes data about age, race, and incidences of osteoporosis, suggests that the total number of fractures alone is not directly correlated with costs.

Table 9 shows the cost burden of osteoporosis by race/ethnicity in 5-year increments from 2005-2025. In this time period, costs are expected to rise 175% among Hispanic and other race/ethnic groups, 79% among African-Americans, and 37% among Caucasians.4

Table 9. Costs of osteoporosis by race or ethnicity, 2005–2025.
Race/Ethnicity Year
2005 2010 2015 2020 2025
Caucasian 14,951 16,188 17,254 18,543 20,548
African American 709 830 959 1,102 1,268
Hispanic 754 1,007 1,305 1,647 2,071
Other 502 655 844 1,077 1,381
Total 16,916 18,680 20,362 22,369 25,268
Note: Costs in $US millions, unadjusted for inflation.

Source: Burge et al. 20074

2.3 LIFE EXPECTANCY AND MORTALITY

Fracture is the most significant clinical manifestation of osteoporosis. While fractures may occur in any bone, they tend to occur at sites of low BMD.2 Hip fractures are the most serious complication of osteoporosis, with almost 50% of patients requiring assistance with activities of daily living such as walking 1 year after occurrence.35 Table 10 summarizes data on 1-year mortality rates associated with osteoporotic hip and vertebral fractures.

Table 10. Mortality rate due to osteoporosis-related fractures.
Fracture Data Source Population 1-Year Mortality Reference
Men Women
Hip fracture Population-based, prospective, matched-pair cohort study (1986-1995), US Adults age ≥ 50 years > 31% 17% Forsen et al. 199936
Vertebral fracture Health Insurance Review Assessment Service (2005-2009), Korea Adults age ≥ 50 years 14.6% 7.16% Lee et al. 2012 37

Abbreviations: US, United States

Among Thai men age ≥ 50 years who sustained a hip fracture following a simple fall, 1-year mortality was 21.1%, approximately 9.3 times the expected mortality rate for this age group. Delayed treatment or the absence of treatment for osteoporosis correlated with higher mortality.38 A similar study of Thai adults age ≥ 50 years, who sustained a hip fracture following a simple fall, reported a 1-year mortality rate of 31% in men, and 16% among women. This study reported that greater mortality was associated with men, age ≥ 70 years, and non-operative treatment.39

Due in part to their greater BMD as compared to Caucasian American women, African American women have about half the rate of hip and vertebral fractures. Even so, mortality following hip fracture is greater among African American women than their Caucasian counterparts, possibly because the former tend to be older at the time of fracture, to have more comorbidities, or to face greater disparities in care. While Caucasian women are about twice as likely to experience hip fractures compared to Caucasian men.40

While osteoporotic fractures are usually precipitated by a fall, they may also occur during routine daily activities. In addition, incident non-traumatic fractures at typical osteoporotic sites (i.e. hip, vertebral, and upper arm fractures) are associated with increased mortality.41 Table 11 presents data on mortality rates in men and women who experienced incident fractures in osteoporotic sites including hip, vertebrae, wrist, and humerus.

Table 11. Mortality rate associated with incident non-traumatic fractures at typical osteoporotic sites.
Data Source Population Type Of Fracture Post-Fracture Mortality Rate Reference
Men Women
Healthcare databases for the Province of Manitoba (1986 -2007; 15-year follow-up), Canada Adults age ≥ 50 years Hip, vertebral, humerus, wrist, among others * 50.1% 44.8% Morin et al. 201041
Multicenter osteoporosis study (1995-1997; 5-year follow-up), Canada Adults age ≥ 50 years Hip 23.5% 23.5% Loannidis et al. 200942
Vertebral 18.2% 15.7%
Forearm or wrist 11.5% 8.1%

Note: *, 66% of fractures were located at sites other than hip and vertebrae

A 34-year prospective observational study assessing the correlation of early menopause and risk of osteoporosis reported that women who underwent menopause before age 47 years had a greater risk of osteoporosis (RR 1.83, 95% CI 1.22-2.74), fragility fracture (RR 1.68, 95% CI 1.05–2.57), and mortality (RR 1.59, 95% CI 1.04-2.36), by age 77 years.43

2.4 KEY TRENDS AND HEALTH OUTCOMES

Measuring BMD is the primary technique for diagnosing and monitoring osteoporosis for postmenopausal women and men age ≥ 50 years.7 Table 12 shows the WHO operational criteria for classifying osteoporosis based on BMD, expressed as a T-score. In brief, the T-score compares a subject’s BMD with the mean value for young normal adult subjects and expresses the difference as a standard deviation.

Table 12. World Health Organization criteria for classification of osteoporosis.
Classification T-score
Normal 0 to -0.99
Osteopenia (low bone density) -1.0 to -2.49
Osteoporosis ≤  -2.5
Severe or established osteoporosis < -2.5 with fracture

Source: World Health Organization. 19941

Some authors have objected to overreliance on T-scores and have pointed out that factors such as family history, laboratory results, genetic influences, or the presence of fragility fractures should be considered along with T-scores.44,45 It has been suggested that additional data be considered when physicians evaluate T-scores.46 For example, the WHO fracture risk assessment tool (FRAX) incorporates dual-energy x-ray absorptiometry (DXA) as well as seven independent risk factors for the assessment of fracture risk in subjects with osteopenia.7,47

As per the Bone Mass Measurement Act of 1998, all US women age >65 years, and men age >70 years are expected to undergo BMD testing. In addition, the 2013 Position Development Conference of the International Society for Clinical Densitometry recommended bone density tests in the presence of risk factors for low bone mass, such as low body weight, prior fracture, high-risk medication use, or diseases or conditions associated with bone loss for both postmenopausal women age <65 years and men age < 70 years.48

Systematic reviews published in 2012 and 2014 addressed the effects of long-term hormone therapy for perimenopausal and postmenopausal women and the effects of steroidal contraceptives on bone fractures in women.49,50 The first review acknowledged that hormone therapy can be effective in preventing postmenopausal osteoporosis, but also noted that the treatment is recommended only for women who are at elevated risk for osteoporosis and have no contraindications, and when non-estrogen therapies are not suitable. The second review examined 19 randomized controlled trials that evaluated the effectiveness of various steroidal contraceptives and noted that none had fracture as an outcome. Reviewers concluded that, based on existing information in 2014, they could not determine if steroidal contraceptives influence fracture risk.

The US Food and Drug Administration (FDA) drugs approved for the treatment of osteoporosis include: calcitonin; bisphosphonates (alendronate, alendronate with cholecalciferol [vitamin D3], ibandronate, risedronate, and zoledronic acid); raloxifene, an estrogen agonist/antagonist; conjugated estrogens/bazedoxifene, a tissue-selective estrogen complex; teriparatide, the 1-34 fragment of parathyroid hormone; and denosumab, an antibody directed against receptor activator of nuclear factor κB ligand (RANKL).51

A review published in 2009 discussed emerging treatments, including agents that show antiresorptive effects and anabolic effects and an agent that may combine both mechanisms of action.52 Other authors have reviewed emerging biologic agents that may help stimulate new bone formation.53

Table 13 summarizes the main currently available pharmacotherapies for treating osteoporosis in the US, along with their benefits and some potential associated adverse effects.54

Table 13. Benefits and adverse effects of pharmacotherapies for osteoporosis treatment.
Pharmacotherapy Efficacy Adverse Effects/Reactions
Bisphosphonates Decreased vertebral, non-vertebral, and hip fractures GI symptoms with oral bisphosphonates; acute-phase reactions with IV bisphosphonates
Raloxifene Decreased vertebral fractures Increased risk of VTE and mortality
Teriparatide Decreased vertebral and non-vertebral fractures Injection site reactions, nausea, dizziness
Denosumab Decreased vertebral, non-vertebral, and hip fractures Eczema, increased risk of cellulitis (in phase 3 clinical trial)
Hormone therapy Decreased vertebral, non-vertebral, and hip fractures Increased risk of VTE, breast cancer, and CV disease in women > 10 years after menopause
Abbreviations: GI, gastrointestinal tract; VTE, venous thromboembolism; CV, cardiovascular; IV, intravenous.
Note: *, GI symptoms include nausea, vomiting, abdominal pain, dyspepsia, esophagitis, or reflux.
Source: Kling et al. 201454

 

Even though older men are twice as likely as women to die after hip fracture,55 osteoporosis is usually considered a “woman’s disease” due to higher overall prevalence in women.56 Due to its higher prevalence, pharmaceutical companies target new drug candidates for the primary prevention of fractures almost exclusively for registration purposes in postmenopausal women.56 Accordingly, there is more evidence on the effects of osteoporosis medications in women than in men.

An Australian study of 1,223 women and 819 men aged ≥ 60 years who were treated with bisphosphonates, hormone therapy (women only), and calcium with or without vitamin D found reduced mortality among women and men who received bisphosphonates.57 A systematic review on the use of bisphosphonates beyond 3 years showed

References

  1. World Health Organization. Assessment of Fractue Risk and Its Application to Screening for Postmenopausal Osteoporosis. Geneva, Switzerland: World Health Organization; 1994.
  2. Watts NB, Bilezikian JP, Camacho PM, Greenspan SL, Harris ST, Hodgson SF, Kleerekoper M, Luckey MM, McClung MR, Pillack RP, Petak SM, AACE Osteoporosis Task Force. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2010;16 Suppl 3:1-37.
  3. Looker AC, Orwoll ES, Johnston CC Jr, Lindsay RL, Wahner HW, Dunn WL, Calvo MS, Harris TB, Heyse SP. Prevalence of low femoral bone density in older U.S. adults from NHANES III. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 1997;12(11):1761-1768.
  4. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2007;22(3):465-475.
  5. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, Haase N, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O’Donnell CJ, Roger V, Rumsfeld J, Sorlie P, Steinberger J, Thom T, Wasserthiel-Smoller S, Hong Y; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115(5):e69-171.
  6. Society AC. Cancer Facts and Figures, 2006. Atlanta, GA: American Cancer Society; 2006.
  7. World Health Organization. Assessment of osteoporosis at the primary health care level. Summary Report of a WHO Scientific Group. 2007; WHO, Geneva. www.who.int/chp/topics/rheumatic/en/index.html. Accessed August 31, 2015.
  8. Takayanagi H. Osteoimmunology and the effects of the immune system on bone. Nature reviews. Rheumatology. 2009;5(12):667-676.
  9. Compton JT, Lee FY. A review of osteocyte function and the emerging importance of sclerostin. The Journal of bone and joint surgery. American volume. 2014;96(19):1659-1668.
  10. Bone HG, Dempster DW, Eisman JA, Greenspan SL, McClung MR, Nakamura T, Papapoulos S, Shih WJ, Rybak-Feiglin A, Santora AC, Verbruggen N, Leung AT, Lombardi A. Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. Osteoporosis International. 2015;26(2):699-712.
  11. Costa AG, Cusano NE, Silva BC, Cremers S, Bilezikian JP. Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis. Nature reviews. Rheumatology. 2011;7(8):447-456.
  12. Leder BZ, O’Dea LS, Zanchetta JR, Kumar P, Banks K, McKay K, Lyttle CR, Hattersley G. Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. The journal of clinical endocrinology and metabolism. 2014;100(2):697-706.
  13. Karsenty G, Oury F. Regulation of male fertility by the bone-derived hormone osteocalcin. Molecular and cellular endocrinology. 2014;382(1):521-526.
  14. Wei J, Ferron M, Clarke CJ, Hannun YA, Jiang H, Blaner WS, Karsenty G. Bone-specific insulin resistance disrupts whole-body glucose homeostasis via decreased osteocalcin activation. The Journal of clinical investigation. 2014;124(4):1-13.
  15. Oury F, Ferron M, Huizhen W, Confavreux C, Xu L, Lacombe J, Srinivas P, Chamouni A, Lugani F, Lejeune H, Kumar TR, Plotton I, Karsenty G. Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. The Journal of clinical investigation. 2013;123(6):2421-2433.
  16. Kajimura D, Lee HW, Riley KJ, Arteaga-Solis E, Ferron M, Zhou B, Clarke CJ, Hannun YA, DePinho RA, Guo XE, Mann JJ, Karsenty G. Adiponectin regulates bone mass via opposite central and peripheral mechanisms through FoxO1. Cell metabolism. 2013;17(6):901-915.
  17. Karsenty G, Ferron M. The contribution of bone to whole-organism physiology. Nature. 2012;481(7381):314-320.
  18. Sims NA, Vrahnas C. Regulation of cortical and trabecular bone mass by communication between osteoblasts, osteocytes and osteoclasts. Archives of biochemistry and biophysics. 2014;561:22-28.
  19. Dallas SL, Prideaux M, Bonewald LF. The osteocyte: an endocrine cell … and more. Endocrine reviews. 2013;34(5):658-690.
  20. Henriksen K, Karsdal MA, Martin TJ. Osteoclast-derived coupling factors in bone remodeling. Calcified tissue international. 2014;94(1):88-97.
  21. Sims NA, Walsh NC. Intercellular cross-talk among bone cells: new factors and pathways. Current osteoporosis reports. 2012;10(2):109-117.
  22. Nishiyama KK, Shane E. Clinical imaging of bone microarchitecture with HR-pQCT. Current osteoporosis reports. 2013;11(2):147-155.
  23. Silva BC, Leslie WD, Resch H, Lamy O, Lesnyak O, Binkley N, McCloskey EV, Kanis JA, Bilezikian JP. Trabecular bone score: a noninvasive analytical method based upon the DXA image. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2014;29(3):518-530.
  24. Sandino C, Kroliczek P, McErlain DD, Boyd SK. Predicting the permeability of trabecular bone by micro-computed tomography and finite element modeling. Journal of biomechanics. 2014;47(12):3129-3134.
  25. Farr JN, Drake MT, Amin S, Melton LJ, 3rd, McCready LK, Khosla S. In vivo assessment of bone quality in postmenopausal women with type 2 diabetes. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2014;29(4):787-795.
  26. Randall C, Bridges D, Guerri R, Nogues X, Puig L, Torres E, Mellibovsky L, Hoffseth K, Stalbaum T, Srikanth A, Weaver JC, Rosen S, Barnard H, Brimer D, Proctor A, Candy J, Saldana C, Chandrasekar S, Lescun T, Nielson CM, Orwoll E, Herthel D, Kopeikin H, Yang HT, Farr JN, McCready L, Khosla S, Diez-Perez A, Hansma PK. Applications of a New Handheld Reference Point Indentation Instrument Measuring Bone Material Strength. Journal of medical devices. 2013;7(4):410051-410056.
  27. Howe TE, Shea B, Dawson LJ, Downie F, Murray A, Ross C, Harbour RT, Caldwell LM, Creed G. Exercise for preventing and treating osteoporosis in postmenopausal women. The Cochrane database of systematic reviews. 2011(7):Cd000333.
  28. Avenell A, Mak JC, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men. The Cochrane database of systematic reviews. 2014;4:Cd000227.
  29. Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, Dawson-Hughes B. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2014;29(11):2520-2526.
  30. Sanders S, Geraci SA. Osteoporosis in postmenopausal women: considerations in prevention and treatment: (women’s health series). Southern medical journal. 2013;106(12):698-706.
  31. Foundation NO. America’s Bone Health: The State of Osteoporosis and low bone mass in our nation. Washington, DC: The Foundation; 2002.
  32. Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet. 2002;359(9319):1761-1767.
  33. Melton LJ, 3rd, Lane AW, Cooper C, Eastell R, O’Fallon WM, Riggs BL. Prevalence and incidence of vertebral deformities. Osteoporosis International. 1993;3(3):113-119.
  34. Clarke BL, Khosla S. Assessing the true impact of recurrent fractures on fracture risk. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2009;24(9):1512-1514.
  35. Orwig DL, Chan J, Magaziner J. Hip fracture and its consequences: differences between men and women. The orthopedic clinics of north america. 2006;37(4):611-622.
  36. Forsen L, Sogaard AJ, Meyer HE, Edna T, Kopjar B. Survival after hip fracture: short- and long-term excess mortality according to age and gender. Osteoporosis International. 1999;10(1):73-78.
  37. Lee YK, Jang S, Jang S, Lee HJ, Park C, Ha YC, Kim DY. Mortality after vertebral fracture in Korea: analysis of the National Claim Registry. Osteoporosis International. 2012;23(7):1859-1865.
  38. Chaysri R, Leerapun T, Klunklin K, Chiewchantanakit S, Luevitoonvechkij S, Rojanasthien S. Factors related to mortality after osteoporotic hip fracture treatment at Chiang Mai University Hospital, Thailand, during 2006 and 2007. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2015;98(1):59-64.
  39. Vaseenon T, Luevitoonvechkij S, Wongtriratanachai P, Rojanasthien S. Long-term mortality after osteoporotic hip fracture in Chiang Mai, Thailand. Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry. 2010;13(1):63-67.
  40. Cauley JA. Defining ethnic and racial differences in osteoporosis and fragility fractures. Clinical orthopaedics and related research. 2011;469(7):1891-1899.
  41. Morin S, Lix LM, Azimaee M, Metge C, Caetano P, Leslie WD. Mortality rates after incident non-traumatic fractures in older men and women. Osteoporos Int. 2011;22(9):2439-2448.
  42. Ioannidis G, Papaioannou A, Hopman WM, Akhtar-Danesh N, Anastassiades T, Pickard L, Kennedy CC, Prior JC, Olszynski WP, Davison KS, Goltzman D, Thabane L, Gafni A, Papadimitropoulos EA, Brown JP, Josse RG, Hanley DA, Adachi JD. Relation between fractures and mortality: results from the Canadian Multicentre Osteoporosis Study. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne. 2009;181(5):265-271.
  43. Svejme O, Ahlborg HG, Nilsson JA, Karlsson MK. Early menopause and risk of osteoporosis, fracture and mortality: a 34-year prospective observational study in 390 women. BJOG : an international journal of obstetrics and gynaecology. 2012;119(7):810-816.
  44. Licata AA. Diagnosing primary osteoporosis: it’s more than a T score. Cleveland Clinic journal of medicine. 2006;73(5):473-476.
  45. Binkley N, Adler R, Bilezikian JP. Osteoporosis diagnosis in men: the T-score controversy revisited. Current osteoporosis reports. 2014;12(4):403-409.
  46. Binkley N, Kiebzak GM, Lewiecki EM, Krueger D, Gangnon RE, Miller PD, Shepherd JA, Drezner MK. Recalculation of the NHANES database SD improves T-score agreement and reduces osteoporosis prevalence. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2005;20(2):195-201.
  47. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19(4):385-397.
  48. Schousboe JT, Shepherd JA, Bilezikian JP, Baim S. Executive summary of the 2013 International Society for Clinical Densitometry Position Development Conference on bone densitometry. Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry. 2013;16(4):455-466.
  49. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women. The Cochrane database of systematic reviews. 2012;7:Cd004143.
  50. Lopez LM, Grimes DA, Schulz KF, Curtis KM, Chen M. Steroidal contraceptives: effect on bone fractures in women. The Cochrane database of systematic reviews. 2014;6:Cd006033.
  51. Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, Lindsay R; National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Osteoporosis International. 2014;25(10):2359-2381.
  52. Clarke BL. New and emerging treatments for osteoporosis. Clinical endocrinology. 2009;71(3):309-321.
  53. Lim V, Clarke BL. New therapeutic targets for osteoporosis: beyond denosumab. Maturitas. 2012;73(3):269-272.
  54. Kling JM, Clarke BL, Sandhu NP. Osteoporosis prevention, screening, and treatment: a review. Journal of women’s health (2002). 2014;23(7):563-572.
  55. Haentjens P, Magaziner J, Colon-Emeric CS, Vanderschueren D, Milisen K, Velkeniers B, Boonen S. Meta-analysis: excess mortality after hip fracture among older women and men. Annals of internal medicine. 2010;152(6):380-390.
  56. Cawthon PM. Gender differences in osteoporosis and fractures. Clinical orthopaedics and related research. 2011;469(7):1900-1905.
  57. Center JR, Bliuc D, Nguyen ND, Nguyen TV, Eisman JA. Osteoporosis medication and reduced mortality risk in elderly women and men. The Journal of clinical endocrinology and metabolism. 2011;96(4):1006-1014.
  58. Eriksen EF, Diez-Perez A, Boonen S. Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review. Bone. 2014;58:126-135.
  59. Modi A, Siris ES, Tang J, Sen S. Cost and consequences of noncompliance with osteoporosis treatment among women initiating therapy. Current medical research and opinion. 2015:1-9.
  60. Caro JJ, Ishak KJ, Huybrechts KF, Raggio G, Naujoks C. The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int. 2004;15(12):1003-1008.
  61. Karaguzel G, Holick MF. Diagnosis and treatment of osteopenia. Reviews in endocrine & metabolic disorders. 2010;11(4):237-251.
  62. Ornstrup MJ, Kjaer TN, Harslof T, Stodkilde-Jorgensen H, Hougaard DM, Cohen A, Pedersen SB, Langdahl BL. Adipose tissue, estradiol levels, and bone health in obese men with metabolic syndrome. European journal of endocrinology / European Federation of Endocrine Societies. 2015;172(2):205-216.
  63. Beerhorst K, Tan IY, De Krom M, Verschuure P, Aldenkamp AP. Antiepileptic drugs and high prevalence of low bone mineral density in a group of inpatients with chronic epilepsy. Acta neurologica Scandinavica. 2013;128(4):273-280.
  64. Looker AC, Melton LJ, 3rd, Harris TB, Borrud LG, Shepherd JA. Prevalence and trends in low femur bone density among older US adults: NHANES 2005-2006 compared with NHANES III. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2010;25(1):64-71.
  65. Bliuc D, Alarkawi D, Nguyen TV, Eisman JA, Center JR. Risk of Subsequent Fractures and Mortality in Elderly Women and Men with Fragility Fractures with and without Osteoporotic Bone Density: The Dubbo Osteoporosis Epidemiology Study. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2015;30(4):637-646.
  66. Eriksen EF. Treatment of osteopenia. Reviews in endocrine & metabolic disorders. 2012;13(3):209-223.
  67. Tufts G. New treatment approach for osteopenia. Journal of midwifery & women’s health. 2011;56(1):61-67.
  68. Meadows ES, Mitchell BD, Bolge SC, Johnston JA, Col NF. Factors associated with treatment of women with osteoporosis or osteopenia from a national survey. BMC women’s health. 2012;12:1.
  69. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2011;96(7):1911-1930.
  70. Ginde AA, Liu MC, Camargo CA, Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Archives of internal medicine. 2009;169(6):626-632.
  71. LeFevre ML, US Preventive Services Task Force. Screening for vitamin D deficiency in adults: U.S. Preventive Services Task Force recommendation statement. Annals of internal medicine. 2015;162(2):133-140.
  72. Binkley N. Vitamin D and osteoporosis-related fracture. Archives of biochemistry and biophysics. 2012;523(1):115-122.
  73. Giangregorio LM, Macintyre NJ, Thabane L, Skidmore CJ, Papaioannou A. Exercise for improving outcomes after osteoporotic vertebral fracture. The Cochrane database of systematic reviews. 2013;1:Cd008618.
  74. Medicine Io. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press; 2010.
  75. Looker AC, Johnson CL, Lacher DA, Pfeiffer CM, Schleicher RL, Sempos CT. Vitamin D status: United States, 2001-2006. NCHS Data Brief. 2011(59):1-8.
  76. Gordon CM, DePeter KC, Feldman HA, Grace E, Emans SJ. Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med. 2004;158(6):531-537.
  77. Rosen CJ, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Manson JE, Mayne ST, Ross AC, Shapses SA, Taylor CL. IOM committee members respond to Endocrine Society vitamin D guideline. The Journal of clinical endocrinology and metabolism. 2012;97(4):1146-1152.
  78. Gahche J, Bailey R, Burt V, Hughes J, Yetley E, Dwyer J, Picciano MF, McDowell M, Sempos C. Dietary supplement use among U.S. adults has increased since NHANES III (1988-1994). NCHS Data Brief. 2011(61):1-8.
  79. Chandler PD, Giovannucci EL, Williams MA, LeBoff MS, Bates DW, Hicks LS. Vitamin D Deficiency Treatment Patterns in Academic Urban Medical Center. The American journal of pharmacy benefits. 2014;6(1):e1-e8.
  80. Shahangian S, Alspach TD, Astles JR, Yesupriya A, Dettwyler WK. Trends in laboratory test volumes for Medicare Part B reimbursements, 2000-2010. Archives of pathology & laboratory medicine. 2014;138(2):189-203.
  81. Winzenberg TM, Powell S, Shaw KA, Jones G. Vitamin D supplementation for improving bone mineral density in children. The Cochrane database of systematic reviews. 2010(10):Cd006944.
  82. Jackson RD, Mysiw WJ. Insights into the epidemiology of postmenopausal osteoporosis: the Women’s Health Initiative. Seminars in reproductive medicine. 2014;32(6):454-462.
  83. Clarke BL. Corticosteroid-induced osteoporosis: an update for dermatologists. American journal of clinical dermatology. 2012;13(3):167-190.
  84. Watts NB, Adler RA, Bilezikian JP, Drake MT, Eastell R, Orwoll ES, Finkelstein JS; Endocrine Society. Osteoporosis in men: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2012;97(6):1802-1822.
  85. Aloia JF, Talwar SA, Pollack S, Yeh J. A randomized controlled trial of vitamin D3 supplementation in African American women. Archives of internal medicine. 2005;165(14):1618-1623.
  86. Nieves JW, Cosman F, Grubert E, Ambrose B, Ralston SH, Lindsay R. Skeletal effects of vitamin D supplementation in postmenopausal black women. Calcified tissue international. 2012;91(5):316-324.
  87. Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet. 2014;383(9912):146-155.
  88. Heaney RP, Holick MF. Why the IOM recommendations for vitamin D are deficient. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2011;26(3):455-457.
  89. Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clinic proceedings. 2011;86(1):50-60.
  90. Moyer VA, Force USPST. Prevention of falls in community-dwelling older adults: U.S. Preventive Services Task Force recommendation statement. Annals of internal medicine. 2012;157(3):197-204.
  91. Moyer VA, US Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force recommendation statement. Annals of internal medicine. 2013;158(9):691-696.
  92. Khan A, Bilezikian J. Primary hyperparathyroidism: pathophysiology and impact on bone. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne. 2000;163(2):184-187.
  93. Griebeler ML, Kearns AE, Ryu E, Hathcock MA, Melton LJ, 3rd, Wermers RA. Secular trends in the incidence of primary hyperparathyroidism over five decades (1965-2010). Bone. 2015;73:1-7.
  94. Fraser WD. Hyperparathyroidism. Lancet. 2009;374(9684):145-158.
  95. Silverberg SJ, Walker MD, Bilezikian JP. Asymptomatic primary hyperparathyroidism. Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry. 2013;16(1):14-21.
  96. Press DM, Siperstein AE, Berber E, Shin JJ, Metzger R, Monteiro R, Mino J, Swagel W, Mitchell JC. The prevalence of undiagnosed and unrecognized primary hyperparathyroidism: a population-based analysis from the electronic medical record. Surgery. 2013;154(6):1232-1237; discussion 1237-1238.
  97. Yeh MW, Ituarte PH, Zhou HC, Nishimoto S, Liu IL, Harari A, Haigh PI, Adams AL. Incidence and prevalence of primary hyperparathyroidism in a racially mixed population. The Journal of clinical endocrinology and metabolism. 2013;98(3):1122-1129.
  98. Wermers RA, Khosla S, Atkinson EJ, Grant CS, Hodgson SF, O’Fallon WM, Melton LJ 3rd. Survival after the diagnosis of hyperparathyroidism: a population-based study. The American journal of medicine. 1998;104(2):115-122.
  99. Clifton-Bligh PB, Nery ML, Supramaniam R, Reeve TS, Delbridge L, Stiel JN, McElduff A, Wilmshurst EG, Robinson BG, Fulcher GR, Learoyd D, Posen S. Mortality associated with primary hyperparathyroidism. Bone. 2015;74:121-124.
  100. Schneider DF, Burke JF, Ojomo KA, Clark N, Mazeh H, Sippel RS, Chen H. Multigland disease and slower decline in intraoperative PTH characterize mild primary hyperparathyroidism. Annals of surgical oncology. 2013;20(13):4205-4211.
  101. Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. The Journal of clinical endocrinology and metabolism. 2014;99(10):3561-3569.
  102. Cusano NE, Silverberg SJ, Bilezikian JP. Normocalcemic primary hyperparathyroidism. Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry. 2013;16(1):33-39.
  103. Silverberg SJ, Clarke BL, Peacock M, Bandeira F, Boutroy S, Cusano NE, Dempster D, Lewiecki EM, Liu JM, Minisola S, Rejnmark L, Silva BC, Walker MD, Bilezikian JP. Current issues in the presentation of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop. The Journal of clinical endocrinology and metabolism. 2014;99(10):3580-3594.
  104. Macfarlane DP, Yu N, Leese GP. Subclinical and asymptomatic parathyroid disease: implications of emerging data. The lancet. Diabetes & endocrinology. 2013;1(4):329-340.
  105. Khan AA. Medical management of primary hyperparathyroidism. Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry. 2013;16(1):60-63.
  106. Lewiecki EM. Management of skeletal health in patients with asymptomatic primary hyperparathyroidism. Journal of clinical densitometry : the official journal of the International Society for Clinical Densitometry. 2010;13(4):324-334.
  107. Dillon ML, Frazee LA. Cinacalcet for the treatment of primary hyperparathyroidism. American journal of therapeutics. 2011;18(4):313-322.
  108. Norlen O, Wang KC, Tay YK, Johnson WR, Grodski S, Yeung M, Serpell J, Sidhu S, Sywak M, Delbridge L. No Need to Abandon Focused Parathyroidectomy: A Multicenter Study of Long-term Outcome After Surgery for Primary Hyperparathyroidism. Annals of surgery. 2014.
  109. Schneider DF, Mazeh H, Sippel RS, Chen H. Is minimally invasive parathyroidectomy associated with greater recurrence compared to bilateral exploration? Analysis of more than 1,000 cases. Surgery. 2012;152(6):1008-1015.
  110. Bilezikian JP, Khan A, Potts JT, Jr., Brandi ML, Clarke BL, Shoback D, Jüppner H, D’Amour P, Fox J, Rejnmark L, Mosekilde L, Rubin MR, Dempster D, Gafni R, Collins MT, Sliney J, Sanders J. Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target-organ involvement, treatment, and challenges for future research. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2011;26(10):2317-2337.
  111. Clarke BL. Bone disease in hypoparathyroidism. Arquivos brasileiros de endocrinologia e metabologia. 2014;58(5):545-552.
  112. Powers J, Joy K, Ruscio A, Lagast H. Prevalence and incidence of hypoparathyroidism in the United States using a large claims database. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2013;28(12):2570-2576.
  113. Kundel A, Thompson GB, Richards ML, Qiu LX, Cai Y, Schwenk FW, Lteif AN, Pittock ST, Kumar S, Tebben PJ, Hay ID, Grant CS. Pediatric endocrine surgery: a 20-year experience at the Mayo Clinic. The Journal of clinical endocrinology and metabolism. 2014;99(2):399-406.
  114. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Postsurgical hypoparathyroidism – risk of fractures, psychiatric diseases, cancer, cataract, and infections. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2014;29(11):2504-2510.
  115. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. The Epidemiology of Non-Surgical Hypoparathyroidism in Denmark: A Nationwide Case Finding Study. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2015.
  116. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L. Cardiovascular and renal complications to postsurgical hypoparathyroidism: a Danish nationwide controlled historic follow-up study. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 2013;28(11):2277-2285.
  117. Mitchell DM, Regan S, Cooley MR, Lauter KB, Vrla MC, Becker CB, Burnett-Bowie SA, Mannstadt M. Long-term follow-up of patients with hypoparathyroidism. The Journal of clinical endocrinology and metabolism. 2012;97(12):4507-4514.
  118. Cusano NE, Rubin MR, McMahon DJ, Irani D, Anderson L, Levy E, Bilezikian JP. PTH(1-84) is associated with improved quality of life in hypoparathyroidism through 5 years of therapy. The Journal of clinical endocrinology and metabolism. 2014;99(10):3694-3699.
  119. Rubin MR, Sliney J, Jr., McMahon DJ, Silverberg SJ, Bilezikian JP. Therapy of hypoparathyroidism with intact parathyroid hormone. Osteoporos Int. 2010;21(11):1927-1934.
  120. Cusano NE, Rubin MR, McMahon DJ, Irani D, Tulley A, Sliney J Jr, Bilezikian JP. The effect of PTH(1-84) on quality of life in hypoparathyroidism. The Journal of clinical endocrinology and metabolism. 2013;98(6):2356-2361.
  121. Sikjaer T, Rolighed L, Hess A, Fuglsang-Frederiksen A, Mosekilde L, Rejnmark L. Effects of PTH(1-84) therapy on muscle function and quality of life in hypoparathyroidism: results from a randomized controlled trial. Osteoporos Int. 2014;25(6):1717-1726.
  122. Singer FR, Bone HG, 3rd, Hosking DJ, Lyles KW, Murad MH, Reid IR, Siris ES; Endocrine Society. Paget’s Disease of Bone: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. 2014;99(12):4408-4422.
  123. Klinck R, Laberge G, Bisson M, McManus S, Michou L, Brown JP, Roux S. Alternative splicing in osteoclasts and Paget’s disease of bone. BMC medical genetics. 2014;15:98.
  124. Ralston SH, Albagha OM. Genetics of Paget’s disease of bone. Current osteoporosis reports. 2014;12(3):263-271.
  125. Bolland MJ, Cundy T. Paget’s disease of bone: clinical review and update. Journal of clinical pathology. 2013;66(11):924-927.
  126. Galson DL, Roodman GD. Pathobiology of Paget’s Disease of Bone. Journal of bone metabolism. 2014;21(2):85-98.
  127. Griz L, Bandeira F, Diniz ET, Cabral M, Freese E. Prevalence of vitamin D deficiency is higher in patients with Paget’s disease of bone compared with age-matched controls. Arquivos brasileiros de endocrinologia e metabologia. 2013;57(7):509-512.
  128. Wat WZ, Cheung WS, Lau TW. A case series of Paget’s disease of bone in Chinese. Hong Kong medical journal = Xianggang yi xue za zhi / Hong Kong Academy of Medicine. 2013;19(3):242-248.
  129. Wat WZ. Current perspectives on bisphosphonate treatment in Paget’s disease of bone. Therapeutics and clinical risk management. 2014;10:977-983.
  130. Maricic M. Zoledronic acid for Paget’s disease of bone. Drugs of today (Barcelona, Spain : 1998). 2007;43(12):879-885.
  131. Keating GM, Scott LJ. Zoledronic acid: a review of its use in the treatment of Paget’s disease of bone. Drugs. 2007;67(5):793-804.
  132. Tziomalos K, Florentin M, Krikis N, Perifanis V, Karagiannis A, Harsoulis F. Persistent effect of zoledronic acid in Paget’s disease. Clinical and experimental rheumatology. 2007;25(3):464-466.
  133. Ruggieri P, Calabro T, Montalti M, Mercuri M. The role of surgery and adjuvants to survival in Pagetic osteosarcoma. Clinical orthopaedics and related research. 2010;468(11):2962-2968.
  134. Gattineni J, Baum M. Regulation of phosphate transport by fibroblast growth factor 23 (FGF23): implications for disorders of phosphate metabolism. Pediatric nephrology (Berlin, Germany). 2010;25(4):591-601.
  135. Mornet E. Hypophosphatasia. Orphanet J Rare Dis. 2007;2:40.
  136. Bianchi ML. Hypophosphatasia: an overview of the disease and its treatment. Osteoporos Int. 2015.
  137. Fraser D. Hypophosphatasia. The American journal of medicine. 1957;22(5):730-746.
  138. Whyte MP. Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocrine reviews. 1994;15(4):439-461.
  139. Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, Downs M, Millán JL, Skrinar AM, Crine P, Landy H. Enzyme-replacement therapy in life-threatening hypophosphatasia. The New England journal of medicine. 2012;366(10):904-913.
  140. Fukumoto S. [Disorders of phosphate metabolism]. Rinsho byori. The Japanese journal of clinical pathology. 2010;58(3):225-231.
  141. Yuan Q, Sitara D, Sato T, Densmore M, Saito H, Schüler C, Erben RG, Lanske B. PTH ablation ameliorates the anomalies of Fgf23-deficient mice by suppressing the elevated vitamin D and calcium levels. Endocrinology. 2011;152(11):4053-4061.
  142. Clarke BL. FGF23 regulation of phosphorus homeostasis is dependent on PTH. Endocrinology. 2011;152(11):4016-4018.
  143. Calvo MS, Uribarri J. Public health impact of dietary phosphorus excess on bone and cardiovascular health in the general population. The American journal of clinical nutrition. 2013;98(1):6-15.
  144. Baker SB, Worthley LI. The essentials of calcium, magnesium and phosphate metabolism: part I. Physiology. Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine. 2002;4(4):301-306.
  145. Baker SB, Worthley LI. The essentials of calcium, magnesium and phosphate metabolism: part II. Disorders. Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine. 2002;4(4):307-315.

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