About

Osteoporosis is defined as a systemic skeletal disease characterized by low mineral bone mass and microarchitectural deterioration of bone tissue, more specifically a decrease in the number of trabeculae coupled to trabecular thinning and loss of connectivity, as well as decrease in cortical thickness and an increase in its porosity. This consequently increases bone fragility and susceptibility to fracture [1]Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med, 1993. 94(6): p. 646-50.

[2]Seeman, E. and P.D. Delmas, Bone quality-the material and structural basis of bone strength and fragility. N Engl J Med, 2006. 354(21): p. 2250-61.

. See bone biology.

normal-bone-osteoporotic-bone

 

The clinical outcome of osteoporosis is fragility fracture(s): broken bones which occur in a setting of low-level or low-energy trauma and that would otherwise not result in a fracture, such as a fall from standing height or less [3]National Institute for Health and Care Excellence NICE: Clinical Guideline [CG146] - Osteoporosis: assessing the risk of fragility fracture. 2012; Available from: https://www.nice.org.uk/guidance/cg146.

. 

Given that only low bone mass can be readily measured in clinical practice, the standard operational definition for the diagnosis of osteoporosis  is the finding of a T-score of ≤ −2.5 at the lumbar spine, femur neck, or total hip, by bone mineral density (BMD) testing using dual-energy X-ray absorptiometry. 

However, as numerous other risk factors contribute to fracture risk in addition to BMD, it is why most guidelines now recommend that a patient with prior low-trauma fracture, or high fracture risk based on FRAX (fracture risk assessment), even without a T-score of −2.5 or lower, be considered for osteoporosis treatment. Overall, clinical judgement remains of upmost importance.

Secondary Osteoporosis

Secondary osteoporosis refers to osteoporosis caused by certain medical conditions or medications that can cause bone loss, increase fracture risk, directly or indirectly affect bone remodelling or interfere with the attainment of peak bone mass in younger individuals. Treatment of secondary osteoporosis is often more complex than treatment of primary osteoporosis, as it depends on the underlying disease. 

Osteoporosis induced by medicines

Adverse effects on bone mineral density (BMD) and/or fracture have been reported for many classes of drugs. Although the link between these medicines and a decrease in BMD and/or an increase in fracture risk incidence has not always been proven as causal, evidence has been reported in the following classes of agents [4]Harvey, N.C., et al., Mind the (treatment) gap: a global perspective on current and future strategies for prevention of fragility fractures. Osteoporos Int, 2017. 28(5): p. 1507-1529.

[5]Panday, K., A. Gona, and M.B. Humphrey, Medication-induced osteoporosis: screening and treatment strategies. Ther Adv Musculoskelet Dis, 2014. 6(5): p. 185-202.

:

  • Androgen deprivation therapy [6]Bienz, M. and F. Saad, Androgen-deprivation therapy and bone loss in prostate cancer patients: a clinical review. Bonekey Rep, 2015. 4: p. 716.

    [7]Rizzoli, R., et al., Cancer-associated bone disease. Osteoporos Int, 2013. 24(12): p. 2929-53.

  • Aromatase inhibitors [7]Rizzoli, R., et al., Cancer-associated bone disease. Osteoporos Int, 2013. 24(12): p. 2929-53.

    [8]Rizzoli, R., et al., Guidance for the prevention of bone loss and fractures in postmenopausal women treated with aromatase inhibitors for breast cancer: an ESCEO position paper. Osteoporos Int, 2012. 23(11): p. 2567-76.

  • Glucocorticoids [9]Whittier, X. and K.G. Saag, Glucocorticoid-induced Osteoporosis. Rheum Dis Clin North Am, 2016. 42(1): p. 177-89, x.

    [10]Lan, G.B., et al., Current Status of Research on Osteoporosis after Solid Organ Transplantation: Pathogenesis and Management. Biomed Res Int, 2015. 2015: p. 413169.

    [11]Kanis, J.A., et al., A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res, 2004. 19(6): p. 893-9.

    [12]Pocket Reference to Osteoporosis, S. Ferrari, Roux, C., Editor 2019, Springer International Publishing.

  • Selective serotonin reuptake inhibitors [13]Rizzoli, R., et al., Antidepressant medications and osteoporosis. Bone, 2012. 51(3): p. 606-13.

  • Thiazolidinediones [14]Palermo, A., et al., Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous? A narrative review. Osteoporos Int, 2015. 26(8): p. 2073-89.

  • Proton pump inhibitors [15]Lau, A.N., et al., The relationship between long-term proton pump inhibitor therapy and skeletal frailty. Endocrine, 2015. 49(3): p. 606-10.

    [16]Yang, Y.X., et al., Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA, 2006. 296(24): p. 2947-53.

    [17]Targownik, L.E., et al., Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ, 2008. 179(4): p. 319-26.

  • Certain immunosuppressants (calmodulin/calcineurin inhibitors) [10]Lan, G.B., et al., Current Status of Research on Osteoporosis after Solid Organ Transplantation: Pathogenesis and Management. Biomed Res Int, 2015. 2015: p. 413169.

  • Hormone deprivation therapy [5]Panday, K., A. Gona, and M.B. Humphrey, Medication-induced osteoporosis: screening and treatment strategies. Ther Adv Musculoskelet Dis, 2014. 6(5): p. 185-202.

  • Certain steroid hormones (medroxyprogesterone acetate, luteinizing hormone releasing hormone agonists) [18]Lopez, L.M., et al., Steroidal contraceptives: effect on bone fractures in women. Cochrane Database Syst Rev, 2014(6): p. CD006033.

  • Certain anticonvulsants, antiepileptic drugs [19]Beerhorst, K., et al., Bone disease during chronic antiepileptic drug therapy: general versus specific risk factors. J Neurol Sci, 2013. 331(1-2): p. 19-25.

  • Anti-coagulants [20]Tufano, A., et al., Oral anticoagulant drugs and the risk of osteoporosis: new anticoagulants better than old? Semin Thromb Hemost, 2015. 41(4): p. 382-8.

  • Chemotherapy agents (methotrexate) [5]Panday, K., A. Gona, and M.B. Humphrey, Medication-induced osteoporosis: screening and treatment strategies. Ther Adv Musculoskelet Dis, 2014. 6(5): p. 185-202.

Other medications or chemicals that have been shown to have adverse effects include thyroid hormone treatment (L-Thyroxine), anxiolytics, sedatives, antidepressants and neuroleptics [21]Vestergaard, P., L. Rejnmark, and L. Mosekilde, Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int, 2006. 17(6): p. 807-16.

, as well as certain antipsychotics (lithium), antacids containing aluminium, cigarette smoking, alcohol abuse, aluminium and barbiturates.

Associations between commonly used drug classes and bone loss and/or fragility fracture incidence are summarised below.

Drug class

Loss of BMD

Increased fracture risk

Literature review

Androgen deprivation therapy (ADT)

Gonadotropin-releasing hormone agonists (GnRHs) are the most commonly used ADT. BMD declines by 2-5% during the first year of ADT.

The risk of hip and vertebral fractures increases to 20-50%
after 5 years of ADT. Fracture risk correlates with age, rate of BMD loss and ADT exposure.

Bienz & Saad, 2015 [6]Bienz, M. and F. Saad, Androgen-deprivation therapy and bone loss in prostate cancer patients: a clinical review. Bonekey Rep, 2015. 4: p. 716.

. 
Rizzoli et al., 2013 [7]Rizzoli, R., et al., Cancer-associated bone disease. Osteoporos Int, 2013. 24(12): p. 2929-53.

.

Aromatase inhibitors (AI)

The annual rate of bone loss in women taking AIs is approx. 2.5% as compared to 1-2% for healthy postmenopausal women.

Women treated with AIs have a 30% higher fracture risk than age-matched healthy women. AI users sustain more peripheral fractures than hip or vertebral fractures.

Rizzoli et al., 2013 [7]Rizzoli, R., et al., Cancer-associated bone disease. Osteoporos Int, 2013. 24(12): p. 2929-53.

.
Rizzoli et al., 2012 [8]Rizzoli, R., et al., Guidance for the prevention of bone loss and fractures in postmenopausal women treated with aromatase inhibitors for breast cancer: an ESCEO position paper. Osteoporos Int, 2012. 23(11): p. 2567-76.

.

 

Glucocorticoids (GC)

While all recipients of GCs are at increased risk of bone loss, older men and postmenopausal women are at highest risk with GC doses of >20 mg daily.

30-50% of patients receiving GCs develop fractures. GC-induced osteocyte apoptosis leads to early increase in fracture risk prior to loss of BMD.

Whittier & Saag, 2016 [9]Whittier, X. and K.G. Saag, Glucocorticoid-induced Osteoporosis. Rheum Dis Clin North Am, 2016. 42(1): p. 177-89, x.

.

Selective serotonin reuptake inhibitors (SSRI)

Small studies have found an association between SSRI use and bone loss. However, meta-analysis has reported SSRI-related fractures in the absence of bone loss.

Two meta-analyses have reported the adjusted odds ratio for fracture among SSRI users to be approx. 1.7. Fracture risk is dependent on dose and duration of SSRI treatment.

Rizzoli et al., 2012 [13]Rizzoli, R., et al., Antidepressant medications and osteoporosis. Bone, 2012. 51(3): p. 606-13.

.

Thiazolidinediones (TZD)

TZDs reduce bone formation through impairing differentiation of osteoblast precursors, and increase resorption through several mechanisms, resulting in bone loss.

Two meta-analyses have reported that TZDs significantly increase fracture incidence in women with Type 2 diabetes, but not in men. Notably, fracture risk is increased in young women without risk factors.

Palermo et al., 2015 [14]Palermo, A., et al., Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous? A narrative review. Osteoporos Int, 2015. 26(8): p. 2073-89.

.
Table adapted from Harvey et al., Osteoporos Int, 2017. 28(5): p. 1507-1529; with permission of Springer. 

The most recurrent cause of secondary osteoporosis is glucocorticoid (GC) treatment. GCs affect the function and numbers of the three major bone cell types (osteoclasts, osteoblasts and osteocytes) [5]Panday, K., A. Gona, and M.B. Humphrey, Medication-induced osteoporosis: screening and treatment strategies. Ther Adv Musculoskelet Dis, 2014. 6(5): p. 185-202.

[22]Henneicke, H., et al., Glucocorticoids and bone: local effects and systemic implications. Trends Endocrinol Metab, 2014. 25(4): p. 197-211.

. The decrease in osteoblast differentiation and the increase apoptosis of both osteoblasts and osteocytes, in addition to the decrease in insulin-like growth factor 1 (IGF-1) due to anti-anabolic effects, all cause bone formation to be impaired [23]Canalis, E., et al., Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int, 2007. 18(10): p. 1319-28.

. As bone loss arises rapidly with GCs, fractures can occur within the first months of GC treatment, underlining the importance in managing these patients as early as possible [12]Pocket Reference to Osteoporosis, S. Ferrari, Roux, C., Editor 2019, Springer International Publishing.

. 

For more information on pathogenesis, prevention and treatment of secondary osteoporosis induced by androgen deprivation therapy, aromatase inhibitors and glucocorticoids, see our ‘Gaps and Solutions in Bone Health’ (pages 7-10).

Individuals who are living with a broad array of diseases can be pre-disposed to develop osteoporosis or sustain fragility fractures. A variety of conditions can increase bone loss, and fracture and/or fall risk by directly or indirectly affecting bone remodelling and/or affecting mobility and balance. Disorders that affect the skeleton include:

  • Autoimmune
    • Rheumatoid arthritis
  • Chronic obstructive pulmonary disease (COPD) and asthma
  • Chronic kidney disease (CKD)
  • Digestive and gastrointestinal (read more in disorders that affect bone nutrition)
    • Diseases of malabsorption (coeliac, Crohn’s, inflammatory bowel disease)
    • Lactose intolerance
  • Endocrine and hormonal
    • Endocrine disorders (e.g. Cushing’s syndrome, hyperparathyroidism, diabetes)
    • Hypogonadal states (male and female; primary or secondary; e.g. Turner syndrome/Kleinfelter syndrome, amenorrhea, Kallmann syndrome)
  • Haematologic
  • Neurological
  • Psychophysiological disorders and mental illness
  • Cancer
  • HIV/AIDS 
  • Some inherited disorders
  • Immobility
  • Chronic disease in childhood

Evidence between common disorders and bone loss and/or fragility fracture incidence is summarised in the table below. 

Disorder

Evidence

Rheumatoid Arthritis (RA)
  • Pro-inflammatory cytokines released into the circulation from the inflamed synovium are thought to cause the bone loss [24]Amarasekara, D.S., J. Yu, and J. Rho, Bone Loss Triggered by the Cytokine Network in Inflammatory Autoimmune Diseases. J Immunol Res, 2015. 2015: p. 832127.

    [25]Van Staa, T.P., et al., Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum, 2006. 54(10): p. 3104-12.

    . 
  • Patients with RA have lower BMD compared to healthy controls and the degree of bone loss observed is correlated with disease severity [26]Lodder, M.C., et al., Bone mineral density in patients with rheumatoid arthritis: relation between disease severity and low bone mineral density. Ann Rheum Dis, 2004. 63(12): p. 1576-80.

    .
  • A large study from the UK found RA patients’ risk of hip fracture and vertebral fracture to be increased 2-fold and 2.4-fold as compared to a control group. The increase in risk is due to both disease activity and its treatment with glucocorticoids [25]Van Staa, T.P., et al., Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum, 2006. 54(10): p. 3104-12.

    . 

Chronic Obstructive Pulmonary Disease (COPD)
  • The average prevalence of osteoporosis among COPD sufferers is of 35% [27]Graat-Verboom, L., et al., Current status of research on osteoporosis in COPD: a systematic review. Eur Respir J, 2009. 34(1): p. 209-18.

    .
  • Vertebral fractures in these patients further compromise their lung function. It is estimated that a single vertebral fracture can cause a 9% reduction in vital capacity [28]Leech, J.A., et al., Relationship of lung function to severity of osteoporosis in women. Am Rev Respir Dis, 1990. 141(1): p. 68-71.

    .
  • In Taiwan, a nationwide population based cohort study reported that COPD sufferers were 24% more likely to sustain an osteoporotic fracture compared to a matched comparator group [29]Lee, P.H., et al., Risk and clinical predictors of osteoporotic fracture in East Asian patients with chronic obstructive pulmonary disease: a population-based cohort study. PeerJ, 2016. 4: p. e2634.

    .

Diseases of malabsorption:
Inflammatory Bowel Disease (IBD)
Coeliac Disease 
Crohn’s Disease
  • Low bone mass is highly prevalent among individuals with coeliac disease [30]Stazi, A.V., A. Trecca, and B. Trinti, Osteoporosis in celiac disease and in endocrine and reproductive disorders. World J Gastroenterol, 2008. 14(4): p. 498-505.

     and Crohn’s disease [31]Schoon, E.J., et al., Osteopenia and osteoporosis in Crohn's disease: prevalence in a Dutch population-based cohort. Scand J Gastroenterol Suppl, 2000(232): p. 43-7.

    [32]Siffledeen, J.S., et al., Bones and Crohn's: risk factors associated with low bone mineral density in patients with Crohn's disease. Inflamm Bowel Dis, 2004. 10(3): p. 220-8.

    . 
  • Many factors contribute to the association between diseases of malabsorption and osteoporosis. These include malabsorption of nutrients, importantly calcium, vitamin D and protein, weight loss/deficit, as well as chronic inflammation (increased levels of circulating cytokines) and use of glucocorticoids.  
  • A large study from Canada reported that the incidence of fracture among individuals with IBD was 40% greater than that of the general population [33]Bernstein, C.N., et al., The incidence of fracture among patients with inflammatory bowel disease. A population-based cohort study. Ann Intern Med, 2000. 133(10): p. 795-9.

    . 
  • Analysis of data from the US National Health and Nutrition Examination Survey (NHANES) demonstrated that coeliac disease is associated with reduced BMD in children and adults aged 18 years and over, and is a risk factor of osteoporotic fractures in men aged 40 years and over [34]Kamycheva, E., T. Goto, and C.A. Camargo, Jr., Celiac disease is associated with reduced bone mineral density and increased FRAX scores in the US National Health and Nutrition Examination Survey. Osteoporos Int, 2017. 28(3): p. 781-790.

    .

Hypogonadism
  • Like oestrogen deficiency in women (which is observed in case of primary or secondary amenorrhea and premature menopause), androgen deficiency in men (primary or secondary hypogonadism) increases the risk of fracture.
  • At any age, acute hypogonadism, such as that resulting from orchidectomy for prostate cancer, accelerates bone loss to a similar rate as seen in menopausal women. The bone loss following orchidectomy is rapid for several years, then reverts to the gradual loss that normally occurs with aging.
  • The Massachusetts Male Aging Study estimated the prevalence of testosterone deficiency in men to be 12.3% among US men aged 40 to 69 years, representing a common contributor to osteoporosis in men [35]Araujo, A.B., et al., Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab, 2004. 89(12): p. 5920-6.

    .

Diabetes
  • Complex pathophysiological mechanisms underlie bone fragility in diabetes mellitus (e.g. hyperglycaemia, oxidative stress and advanced glycation end-product accumulation). Among other factors, the antidiabetic medications, thiazolidinediones also have a role to play in bone and mineral metabolism [36]Napoli, N., et al., Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol, 2017. 13(4): p. 208-219.

    .
  • Despite often having normal to high BMD, individuals with type 2 diabetes have increased fracture risk irrespective of sex, race or ethnicity. Accordingly, BMD measurements may underestimate skeletal fragility in type 2 diabetics. In the absence of evidence to the contrary, management should adhere to the established principles of management of postmenopausal osteoporosis [37]Shanbhogue, V.V., et al., Type 2 diabetes and the skeleton: new insights into sweet bones. Lancet Diabetes Endocrinol, 2016. 4(2): p. 159-73.

    [38]Ferrari, S.L., et al., Diagnosis and management of bone fragility in diabetes: an emerging challenge. Osteoporos Int, 2018. 29(12): p. 2585-2596.

    .
  • Both Type 1 and Type 2 diabetics are at increased risk of sustaining hip fractures. A systematic review estimated the relative risks to be 6.3-6.9 and 1.4-1.7 for Type 1 and Type 2, respectively [39]Janghorbani, M., et al., Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol, 2007. 166(5): p. 495-505.

    [40]Hough, F.S., et al., MECHANISMS IN ENDOCRINOLOGY: Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus. Eur J Endocrinol, 2016. 174(4): p. R127-38.

    .

Dementia
  • A significant overlap exists between sufferers of dementia and older people at high risk of injurious falls and fractures; this is particularly evident amongst patients presenting with hip fracture. A UK study found that during a 12 month period, 66% of participants with dementia had a fall compared to 36% in age-matched controls [41]Allan, L.M., et al., Incidence and prediction of falls in dementia: a prospective study in older people. PLoS One, 2009. 4(5): p. e5521.

    .
  • Also in the UK, the incidence of hip fracture among patients with Alzheimer’s disease is three times higher than among cognitively healthy peers [42]Baker, N.L., et al., Hip fracture risk and subsequent mortality among Alzheimer's disease patients in the United Kingdom, 1988-2007. Age Ageing, 2011. 40(1): p. 49-54.

    .
  • A meta-analysis estimated the prevalence of cognitive impairment amongst older hip fracture patients at 42% and of dementia at 19% [43]Seitz, D.P., et al., Prevalence of dementia and cognitive impairment among older adults with hip fractures. J Am Med Dir Assoc, 2011. 12(8): p. 556-564.

    .

Chronic Kidney Disease (CKD)
  • Patients with dialysis dependent end-stage renal disease (ESRD) sustain fractures at a rate approximately 4-fold higher than the general population [44]Elliott, M.J., et al., Estimated GFR and fracture risk: a population-based study. Clin J Am Soc Nephrol, 2013. 8(8): p. 1367-76.

    .
  • Among patients with less severe renal dysfunction, decreasing estimated glomerular filtration rate (eGFR) has been shown to be associated with increased risk of hip fracture [45]Ensrud, K.E., et al., Renal function and risk of hip and vertebral fractures in older women. Arch Intern Med, 2007. 167(2): p. 133-9.

    .

Chronic Kidney Disease (CKD)
  • Many chronic/serious conditions occurring in childhood (e.g. inflammatory bowel disease, juvenile idiopathic arthritis, malignancy), may impair skeletal health directly, or as a consequence of treatment (e.g. corticosteroids). Low peak bone mass and increased risk of osteoporosis in older age may result.
For more information on diseases (COPD, diseases of malabsorption, RA, hypogonadism, dementia and diabetes) associated with osteoporosis, see our ‘Gaps and Solutions in Bone Health ’ (pages 11-14).

REFERENCES

1.
Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med, 1993. 94(6): p. 646-50.
2.
Seeman, E. and P.D. Delmas, Bone quality-the material and structural basis of bone strength and fragility. N Engl J Med, 2006. 354(21): p. 2250-61.
3.
National Institute for Health and Care Excellence NICE: Clinical Guideline [CG146] - Osteoporosis: assessing the risk of fragility fracture. 2012; Available from: https://www.nice.org.uk/guidance/cg146.
4.
Harvey, N.C., et al., Mind the (treatment) gap: a global perspective on current and future strategies for prevention of fragility fractures. Osteoporos Int, 2017. 28(5): p. 1507-1529.
5.
Panday, K., A. Gona, and M.B. Humphrey, Medication-induced osteoporosis: screening and treatment strategies. Ther Adv Musculoskelet Dis, 2014. 6(5): p. 185-202.
6.
Bienz, M. and F. Saad, Androgen-deprivation therapy and bone loss in prostate cancer patients: a clinical review. Bonekey Rep, 2015. 4: p. 716.
7.
Rizzoli, R., et al., Cancer-associated bone disease. Osteoporos Int, 2013. 24(12): p. 2929-53.
8.
Rizzoli, R., et al., Guidance for the prevention of bone loss and fractures in postmenopausal women treated with aromatase inhibitors for breast cancer: an ESCEO position paper. Osteoporos Int, 2012. 23(11): p. 2567-76.
9.
Whittier, X. and K.G. Saag, Glucocorticoid-induced Osteoporosis. Rheum Dis Clin North Am, 2016. 42(1): p. 177-89, x.
10.
Lan, G.B., et al., Current Status of Research on Osteoporosis after Solid Organ Transplantation: Pathogenesis and Management. Biomed Res Int, 2015. 2015: p. 413169.
11.
Kanis, J.A., et al., A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res, 2004. 19(6): p. 893-9.
12.
Pocket Reference to Osteoporosis, S. Ferrari, Roux, C., Editor 2019, Springer International Publishing.
13.
Rizzoli, R., et al., Antidepressant medications and osteoporosis. Bone, 2012. 51(3): p. 606-13.
14.
Palermo, A., et al., Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous? A narrative review. Osteoporos Int, 2015. 26(8): p. 2073-89.
15.
Lau, A.N., et al., The relationship between long-term proton pump inhibitor therapy and skeletal frailty. Endocrine, 2015. 49(3): p. 606-10.
16.
Yang, Y.X., et al., Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA, 2006. 296(24): p. 2947-53.
17.
Targownik, L.E., et al., Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ, 2008. 179(4): p. 319-26.
18.
Lopez, L.M., et al., Steroidal contraceptives: effect on bone fractures in women. Cochrane Database Syst Rev, 2014(6): p. CD006033.
19.
Beerhorst, K., et al., Bone disease during chronic antiepileptic drug therapy: general versus specific risk factors. J Neurol Sci, 2013. 331(1-2): p. 19-25.
20.
Tufano, A., et al., Oral anticoagulant drugs and the risk of osteoporosis: new anticoagulants better than old? Semin Thromb Hemost, 2015. 41(4): p. 382-8.
21.
Vestergaard, P., L. Rejnmark, and L. Mosekilde, Anxiolytics, sedatives, antidepressants, neuroleptics and the risk of fracture. Osteoporos Int, 2006. 17(6): p. 807-16.
22.
Henneicke, H., et al., Glucocorticoids and bone: local effects and systemic implications. Trends Endocrinol Metab, 2014. 25(4): p. 197-211.
23.
Canalis, E., et al., Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int, 2007. 18(10): p. 1319-28.
24.
Amarasekara, D.S., J. Yu, and J. Rho, Bone Loss Triggered by the Cytokine Network in Inflammatory Autoimmune Diseases. J Immunol Res, 2015. 2015: p. 832127.
25.
Van Staa, T.P., et al., Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis. Arthritis Rheum, 2006. 54(10): p. 3104-12.
26.
Lodder, M.C., et al., Bone mineral density in patients with rheumatoid arthritis: relation between disease severity and low bone mineral density. Ann Rheum Dis, 2004. 63(12): p. 1576-80.
27.
Graat-Verboom, L., et al., Current status of research on osteoporosis in COPD: a systematic review. Eur Respir J, 2009. 34(1): p. 209-18.
28.
Leech, J.A., et al., Relationship of lung function to severity of osteoporosis in women. Am Rev Respir Dis, 1990. 141(1): p. 68-71.
29.
Lee, P.H., et al., Risk and clinical predictors of osteoporotic fracture in East Asian patients with chronic obstructive pulmonary disease: a population-based cohort study. PeerJ, 2016. 4: p. e2634.
30.
Stazi, A.V., A. Trecca, and B. Trinti, Osteoporosis in celiac disease and in endocrine and reproductive disorders. World J Gastroenterol, 2008. 14(4): p. 498-505.
31.
Schoon, E.J., et al., Osteopenia and osteoporosis in Crohn's disease: prevalence in a Dutch population-based cohort. Scand J Gastroenterol Suppl, 2000(232): p. 43-7.
32.
Siffledeen, J.S., et al., Bones and Crohn's: risk factors associated with low bone mineral density in patients with Crohn's disease. Inflamm Bowel Dis, 2004. 10(3): p. 220-8.
33.
Bernstein, C.N., et al., The incidence of fracture among patients with inflammatory bowel disease. A population-based cohort study. Ann Intern Med, 2000. 133(10): p. 795-9.
34.
Kamycheva, E., T. Goto, and C.A. Camargo, Jr., Celiac disease is associated with reduced bone mineral density and increased FRAX scores in the US National Health and Nutrition Examination Survey. Osteoporos Int, 2017. 28(3): p. 781-790.
35.
Araujo, A.B., et al., Prevalence and incidence of androgen deficiency in middle-aged and older men: estimates from the Massachusetts Male Aging Study. J Clin Endocrinol Metab, 2004. 89(12): p. 5920-6.
36.
Napoli, N., et al., Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol, 2017. 13(4): p. 208-219.
37.
Shanbhogue, V.V., et al., Type 2 diabetes and the skeleton: new insights into sweet bones. Lancet Diabetes Endocrinol, 2016. 4(2): p. 159-73.
38.
Ferrari, S.L., et al., Diagnosis and management of bone fragility in diabetes: an emerging challenge. Osteoporos Int, 2018. 29(12): p. 2585-2596.
39.
Janghorbani, M., et al., Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol, 2007. 166(5): p. 495-505.
40.
Hough, F.S., et al., MECHANISMS IN ENDOCRINOLOGY: Mechanisms and evaluation of bone fragility in type 1 diabetes mellitus. Eur J Endocrinol, 2016. 174(4): p. R127-38.
41.
Allan, L.M., et al., Incidence and prediction of falls in dementia: a prospective study in older people. PLoS One, 2009. 4(5): p. e5521.
42.
Baker, N.L., et al., Hip fracture risk and subsequent mortality among Alzheimer's disease patients in the United Kingdom, 1988-2007. Age Ageing, 2011. 40(1): p. 49-54.
43.
Seitz, D.P., et al., Prevalence of dementia and cognitive impairment among older adults with hip fractures. J Am Med Dir Assoc, 2011. 12(8): p. 556-564.
44.
Elliott, M.J., et al., Estimated GFR and fracture risk: a population-based study. Clin J Am Soc Nephrol, 2013. 8(8): p. 1367-76.
45.
Ensrud, K.E., et al., Renal function and risk of hip and vertebral fractures in older women. Arch Intern Med, 2007. 167(2): p. 133-9.