Osteoporosis

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Osteoporosis, which literally means "porous bone", is a disease in which the density and quality of bone are reduced. As the bones become more porous and fragile, the risk of fracture is greatly increased. The loss of bone occurs "silently" and progressively. Often there are no symptoms until the first fracture occurs.
—The International Osteoporosis Foundation (IOF)
Osteoporosis is characterized by decreased bone mass and quality. Causes of osteoporosis may be hereditary and/or environmental. Osteoporosis symptoms usually go unnoticed until development of skeletal fracture. Osteoporosis treatment includes medications, exercises, and possibly surgery. Osteoporosis drugs include bisphosphonates, selective estrogen receptor modulators, and calcitonin. Calcium and vitamin D supplementation and weight-bearing exercise are the mainstays of osteoporosis prevention.
—Osteoporosis Resource Center
Osteoporosis means “porous bone.” If you look at healthy bone under a microscope, you will see that parts of it look like a honeycomb. If you have osteoporosis, the holes and spaces in the honeycomb are much bigger than they are in healthy bone. This means your bones have lost density or mass. It also means that the structure of your bone tissues has become abnormal. As your bones become less dense, they become weaker.
—The National Osteoporosis Foundation

Osteoporosis is "reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis (osteoporosis, postmenopausal) and age-related or senile osteoporosis."[1][2]

Although more common in women, osteoporosis may occur in males.[3]

Clinical practice guidelines are available.[4][5]

Causes/etiology

One of every eight hip fractures may be due to smoking of tobacco.[6]

Subclinical hypercortisolism may underlie about 5% of cases of osteoporosis.[7] These patients can be identified by serum cortisol levels greater than 50.0 nmol/L after a 1-mg overnight dexamethasone test.

Glucocorticoid drugs can cause osteoporosis.

Diagnosis

Diagnosis is made be bone densitometry, or by the presence of fragility fractures. However, high-trauma fractures also are associated with osteoporosis.[8]

History and physical examination

A systematic review by the Rational Clinical Examination concluded that the best physical findings in women are:[9]

  • weight less than 51 kg
  • tooth count less than 20
  • rib-pelvis distance less than 2 finger breadths
  • wall-occiput distance greater than 0 cm
  • self-reported humped back

For men, the "MORES" clinical prediction rule uses age, weight, and history of chronic obstructive pulmonary disease to predict risk of a fracture with a number needed to screen of 279 to prevent one fracture:[10]

Bone densitometry

For more information, see: Photon absorptiometry.


Densitometry using photon absorptiometry is scored by two measures, the T-score and the Z-score. Scores indicate the amount one's bone mineral density varies from the mean. Negative scores indicate lower bone density, and positive scores indicate higher.

T-score

The T-score is a comparison of a patient's bone density to that of a healthy thirty-year-old. The criteria of the World Health Organization are[11]:

  • Osteoporosis is defined as -2.5 or lower, meaning a bone density that is two and a half standard deviations below the mean of a thirty year old woman.
  • Osteopenia is defined as less than -1.0 and greater than -2.5
  • Normal is a T-score of -1.0 or higher

Z-score

The Z-score is a comparison of a patient's bone density to the average bone density of their, sex, and race. This value is used in premenopausal women, men under aged 50, and in children.[12]

Other tests

Screening patients for hypercortisolism with a 2-day, low-dose dexamethasone suppression test ( 0.5 mg of dexamethasone by mouth every 6 hours followed by measurement of serum cortisol at 9:00 a.m. 2 days after the first dose), may identify hypercortisolism in 10% of patients who have both T-scores of –2.5 or less and vertebral fractures.[13]

Screening

Females

The US Preventive Services Task Force, originally in 2002[14] with 2010 update[15][16], recommends screening women if:

  • women aged 65 years or older

Interval for repeating screening is uncertain.

Tools for assessing risk include:

The National Osteoporosis Foundation recommends screening women if:[5]

  • 65 years of age or older
  • "Women in the menopausal transition if there is a specific risk factor associated with increased fracture risk such as low body weight, prior low-trauma fracture or high risk medication"
  • Fracture after age 50
  • "A condition (e.g., rheumatoid arthritis) or taking a medication (e.g., glucocorticoids in a daily dose ≥ 5 mg prednisone or equivalent for ≥ three months) associated with low bone mass or bone loss"
  • Low body weight
Clinical prediction rules for osteoporosis[17][18][19][20][21]
  Outcome Sensitivity Specificity For 5% prevalence of osteoporosis
as reported by WHI[17]
Positive predictive value Negative predictive value
Women’s Health Initiative (WHI) Hip Fracture Risk Calculator[17] > 1% estimated risk of fracture (≥ 18 points) • T-score < –2.5 SD by photon absorptiometry
• Fracture (using ≥ 21 points)		 22%[17]

50%[17]		 96%[17]

85%[17]		 22% 4.1%
Osteoporosis Self-Assessment Tool (OST)[19] < 2 • T-score < –2.5 SD by photon absorptiometry at femoral neck or lumbar spine 69%[20] 59%[20] 8% 2.7%
Osteoporosis Risk Assessment Instrument (ORAI)[18] ≥ 9 • T-score < –2.5 SD by photon absorptiometry at femoral neck or lumbar spine 64%[20] 59%[20] 8% 3.1%
• T-score < –2.5 SD by photon absorptiometry at femoral neck 98%[21] 28%[21] 7% 0.4%
Body weight[21] < 70 kg • T-score < –2.5 SD by photon absorptiometry at femoral neck 87%[20] 48%[20] 8% 1.4%

Clinical prediction rules are available to guide selection of women for screening. The Osteoporosis Self-Assessment Tool (OST)[19] may be the most sensitive strategy for detecting abnormal bone density according to a meta-analysis in 2007.[20][21] More recently, a clinical prediction rule for women developed from the WHI studies (http://hipcalculator.fhcrc.org/) is available to predict risk of a fracture over five years. [17] Of note, the clinical prediction rule did not study the contribution of physical examination findings.

Unfortunately, all current guidelines and prediction rules ignore the role of risk factors for accidental falls.[22]

Males

A cost-benefit analysis concluded that "bone densitometry followed by bisphosphonate therapy for those with osteoporosis may be cost-effective for men aged 65 years or older with a self-reported prior clinical fracture and for men aged 80 to 85 years with no prior fracture."[23]

A clinical practice guideline[24] and systematic review[25] by the American College of Physicians recommends "clinicians obtain DXA [dual-energy x-ray absorptiometry] for men who are at increased risk for osteoporosis and are candidates for drug therapy." However, the College did not define increased risk.

Prevention and treatment

Clinical practice guidelines are available.[26][27][28][16] The National Osteoporosis Foundation recommends treating women if:[26]

  • T-score ≤ -2.5
  • Low bone mass (T-score between -1.0 and -2.5) and ≥ 3% 10-year hip fracture probability. This threshold was determined by a cost-benefit analysis.[29]

It is not clear which medications are best for treating osteoporosis.[30]

In monitoring bone mineral density, the least significant change is defined as "defined as a change that is 2.8 times the precision error for each measured site, for each technologist, and it is best expressed as an absolute value (g/cm2)".[31]

Special consideration is needed for patients taking glucocorticoids.

Calcium

A meta-analysis of randomized controlled trials concluded "Evidence supports the use of calcium, or calcium in combination with vitamin D supplementation, in the preventive treatment of osteoporosis in people aged 50 years or older. For best therapeutic effect, we recommend minimum doses of 1200 mg of calcium, and 800 IU of vitamin D (for combined calcium plus vitamin D supplementation)."[13]

Calcium supplementation may increase rates of myocardial infarction.[32]

Vitamin D

Vitamin D is only effective if given with calcium.[33] Vitamin D may also prevent accidental falls by increasing muscle strength.[34]

Antiresorptive medications

Bisphosphonates

Bisophosphonates may be cost-effective when the 10 year risk of fracture is 3% (see osteoporosis#prognosis below).[29] Once yearly, intravenous zoledronic acid reduced second hip fractures in a randomized controlled trial of women after an initial hip fracture. In this trial, 19 patients had to be treated for one hip fracture to be prevented.[35]

Alendronate reduces clinical fractures by 36% in women with osteoporosis.[36] The benefit is stronger for women with existing vertebral fractures.[37]

The effects of alendronate may continue through 10 years of treatment according to the FLEX randomized controlled trial which included women with T-scores of -1.6 or worse.[38] However, the FLEX trial found increased wrist fractures with long term treatment. This increase may be due to "oversuppressing bone turnover that could, potentially, impair some of the biomechanical properties of bone. High doses of bisphosphonates result in accumulation of microdamage in the bones of dogs, but the relevance of these findings in terms of bone strength and clinical use is unclear."[39]

Calcitonin

Selective Estrogen Receptor Modulators (SERMs)

Denosumab

Denosumab is a humanized monoclonal antibody that inhibits osteoclasts.[40]

Anabolic medications

As opposed to antiresorptive drugs, anabolic drugs enhance bone formation.[41]

Parathyroid hormone

Sodium fluoride

Strontium Ranelate

Strontium Ranelate has both anti-resorptive and anabolic mechanisms.[42]

Prognosis

A bone density of one standard deviation below age adjusted mean approximately doubles the risk of fracture.[43]

After started treatment with a bisphosphonate it may not help to repeat measurements of bone density. [44]

FRAX tool

Improvements in the prediction of hip fracture by adding the FRAX to the bone density.[45]
  Sensitivity
(taken from Table 1 of Johansson)		 Specificity
(calculated from Table 1 of Johansson)		 Positive predictive value Number with abnormal result needed to treat to prevent one fracture†
Bone density < unstated value 56% 79% 6% 47
Bone density plus FRAX[46] > 3.7% 56% 84% 8% 33
† This is calculated by (100/(PPV*0.35) and assumes biphosphonate reduces fractures by 35% as found in the FIT trial[36].

The risk of fracture can be estimated by the Fracture Risk Assessment Tool (FRAX). This tool was recommended by the WHO Scientific Group on the Assessment of Osteoporosis at Primary Health Care Level during their 2004 meeting.[47] Interpretation of the ability of the FRAX is hindered by their publications not following guidelines for reporting of studies of diagnostic tests as as the STARD. In addition, development of the tool may be affected by conflict of interest.[48] Also, the FRAX developers may have changed their calculations within the tool without publishing the changes or their reason.[49]

The FRAX tool may not be better than using bone density and age alone.[50]

QFracture

The QFracture tool (http://www.qfracture.org/) may be more accurate than the FRAX.[51] However, QFracture does not incorporate bone density.

See also

References

  1. ↑ Anonymous. Osteoporosis. National Library of Medicine. Retrieved on 2008-01-08.
  2. ↑ Sambrook P, Cooper C (2006). "Osteoporosis". Lancet 367 (9527): 2010–8. DOI:10.1016/S0140-6736(06)68891-0. PMID 16782492. Research Blogging.
  3. ↑ Ebeling PR (April 2008). "Clinical practice. Osteoporosis in men". N. Engl. J. Med. 358 (14): 1474–82. DOI:10.1056/NEJMcp0707217. PMID 18385499. Research Blogging.
  4. ↑ (2010 Jan-Feb) "Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society.". Menopause 17 (1): 25-54; quiz 55-6. DOI:10.1097/gme.0b013e3181c617e6. PMID 20061894. Research Blogging.
  5. ↑ 5.0 5.1 National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation;2008.
  6. ↑ Law MR, Hackshaw AK (October 1997). "A meta-analysis of cigarette smoking, bone mineral density and risk of hip fracture: recognition of a major effect". BMJ 315 (7112): 841–6. PMID 9353503. PMC 2127590. [e]
  7. ↑ Chiodini I, Mascia ML, Muscarella S, et al (2007). "Subclinical hypercortisolism among outpatients referred for osteoporosis". Ann. Intern. Med. 147 (8): 541–8. PMID 17938392. [e]
  8. ↑ Mackey DC, Lui LY, Cawthon PM, et al (2007). "High-trauma fractures and low bone mineral density in older women and men". JAMA 298 (20): 2381–8. DOI:10.1001/jama.298.20.2381. PMID 18042915. Research Blogging.
  9. ↑ Green AD, Colón-Emeric CS, Bastian L, Drake MT, Lyles KW (2004). "Does this woman have osteoporosis?". JAMA 292 (23): 2890–900. DOI:10.1001/jama.292.23.2890. PMID 15598921. Research Blogging.
  10. ↑ Shepherd AJ, Cass AR, Carlson CA, Ray L (2007). "Development and internal validation of the male osteoporosis risk estimation score". Ann Fam Med 5 (6): 540–6. DOI:10.1370/afm.753. PMID 18025492. Research Blogging. (Prediction rule in Table 4)
  11. ↑ WHO Scientific Group on the Prevention and Management of Osteoporosis (2000 : Geneva, Switzerland) (2003). Prevention and management of osteoporosis : report of a WHO scientific group (pdf). Retrieved on 2007-05-31.
  12. ↑ Raisz LG (July 2005). "Clinical practice. Screening for osteoporosis". N. Engl. J. Med. 353 (2): 164–71. DOI:10.1056/NEJMcp042092. PMID 16014886. Research Blogging.
  13. ↑ 13.0 13.1 Chiodini, Iacopo, Maria Lucia Mascia, Silvana Muscarella, Claudia Battista, Salvatore Minisola, Maura Arosio, et al. 2007. Subclinical Hypercortisolism among Outpatients Referred for Osteoporosis. Ann Intern Med 147, no. 8 (October 16): 541-548. http://www.annals.org/cgi/content/abstract/147/8/541 (accessed October 16, 2007). Cite error: Invalid <ref> tag; name "pmidpending" defined multiple times with different content
  14. ↑ (2002) "Screening for osteoporosis in postmenopausal women: recommendations and rationale". Ann. Intern. Med. 137 (6): 526-8. PMID 12230355. [e]
  15. ↑ U.S. Preventive Services Task Force (2011). "Screening for osteoporosis: u.s. Preventive services task force recommendation statement.". Ann Intern Med 154 (5): 356-64. DOI:10.1059/0003-4819-154-5-201103010-00307. PMID 21242341. Research Blogging.
  16. ↑ 16.0 16.1 Nelson HD, Haney EM, Dana T, Bougatsos C, Chou R (2010). "Screening for Osteoporosis: An Update for the U.S. Preventive Services Task Force.". Ann Intern Med. DOI:10.1059/0003-4819-153-2-201007200-00262. PMID 20621892. Research Blogging. Cite error: Invalid <ref> tag; name "pmid20621892" defined multiple times with different content
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 17.7 Robbins J, Aragaki AK, Kooperberg C, et al (2007). "Factors associated with 5-year risk of hip fracture in postmenopausal women". JAMA 298 (20): 2389–98. DOI:10.1001/jama.298.20.2389. PMID 18042916. Research Blogging. Sensitivy and specificy in detecting abnormal bone density is in Table 5 Cite error: Invalid <ref> tag; name "pmid18042916" defined multiple times with different content
  18. ↑ 18.0 18.1 Cadarette SM, Jaglal SB, Kreiger N, McIsaac WJ, Darlington GA, Tu JV (May 2000). "Development and validation of the Osteoporosis Risk Assessment Instrument to facilitate selection of women for bone densitometry". CMAJ 162 (9): 1289–94. PMID 10813010. PMC 1232411. [e]
  19. ↑ 19.0 19.1 19.2 Koh LK, Sedrine WB, Torralba TP, et al. (2001). "A simple tool to identify asian women at increased risk of osteoporosis". Osteoporos Int 12 (8): 699–705. PMID 11580084. [e]
  20. ↑ 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 Martínez-Aguilà D, Gómez-Vaquero C, Rozadilla A, Romera M, Narváez J, Nolla JM (2007). "Decision rules for selecting women for bone mineral density testing: application in postmenopausal women referred to a bone densitometry unit". J. Rheumatol. 34 (6): 1307-12. PMID 17552058. [e]
  21. ↑ 21.0 21.1 21.2 21.3 21.4 Cadarette SM, Jaglal SB, Murray TM, McIsaac WJ, Joseph L, Brown JP (July 2001). "Evaluation of decision rules for referring women for bone densitometry by dual-energy x-ray absorptiometry". JAMA 286 (1): 57–63. PMID 11434827. [e]
  22. ↑ Cummings SR, Nevitt MC, Browner WS, et al. (March 1995). "Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group". N. Engl. J. Med. 332 (12): 767–73. PMID 7862179. [e]
  23. ↑ Schousboe JT, Taylor BC, Fink HA, et al (August 2007). "Cost-effectiveness of bone densitometry followed by treatment of osteoporosis in older men". JAMA 298 (6): 629–37. DOI:10.1001/jama.298.6.629. PMID 17684185. Research Blogging.
  24. ↑ Qaseem A, Snow V, Shekelle P, Hopkins R, Forciea MA, Owens DK (May 2008). "Screening for osteoporosis in men: a clinical practice guideline from the American College of Physicians". Ann. Intern. Med. 148 (9): 680–4. PMID 18458281. [e]
  25. ↑ Liu H, Paige NM, Goldzweig CL, et al (May 2008). "Screening for osteoporosis in men: a systematic review for an American College of Physicians guideline". Ann. Intern. Med. 148 (9): 685–701. PMID 18458282. [e]
  26. ↑ 26.0 26.1 National Osteoporosis Foundation. Clinician's Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation;2008.
  27. ↑ Hodgson SF, Watts NB, Bilezikian JP, Clarke BL, Gray TK, Harris DW et al. (2003). "American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003.". Endocr Pract 9 (6): 544-64. PMID 14715483. AACE website
  28. ↑ Qaseem A, Snow V, Shekelle P, Hopkins R, Forciea MA, Owens DK et al. (2008). "Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians.". Ann Intern Med 149 (6): 404-15. PMID 18794560. National Guidelines Clearinghouse
  29. ↑ 29.0 29.1 Tosteson AN, Melton LJ, Dawson-Hughes B, et al. (April 2008). "Cost-effective osteoporosis treatment thresholds: the United States perspective". Osteoporos Int 19 (4): 437–47. DOI:10.1007/s00198-007-0550-6. PMID 18292976. Research Blogging. Cite error: Invalid <ref> tag; name "pmid18292976" defined multiple times with different content
  30. ↑ Maclean C, Newberry S, Maglione M, et al (2007). "Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis". Ann Intern Med. PMID 18087050. [e]
  31. ↑ Lenchik L, Kiebzak GM, Blunt BA, International Society for Clinical Densitometry Position Development Panel and Scientific Advisory Committee (2002). "What is the role of serial bone mineral density measurements in patient management?". J Clin Densitom 5 Suppl: S29-38. PMID 12464709. [e]
  32. ↑ Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD et al. (2010). "Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis.". BMJ 341: c3691. DOI:10.1136/bmj.c3691. PMID 20671013. PMC PMC2912459. Research Blogging.
  33. ↑ DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group (2010). "Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe.". BMJ 340: b5463. DOI:10.1136/bmj.b5463. PMID 20068257. Research Blogging.
  34. ↑ Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R et al. (2009). "Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials.". BMJ 339: b3692. DOI:10.1136/bmj.b3692. PMID 19797342. Research Blogging.
  35. ↑ Lyles KW, Colón-Emeric CS, Magaziner JS, et al (2007). "Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture". N Engl J Med. DOI:10.1056/NEJMoa074941. PMID 17878149. Research Blogging.
  36. ↑ 36.0 36.1 Cummings SR, Black DM, Thompson DE, et al. (1998). "Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial". JAMA 280 (24): 2077–82. PMID 9875874. [e]
  37. ↑ Black DM, Cummings SR, Karpf DB, et al. (December 1996). "Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group". Lancet 348 (9041): 1535–41. PMID 8950879. [e]
  38. ↑ Black DM, Schwartz AV, Ensrud KE, et al (December 2006). "Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial". JAMA : the journal of the American Medical Association 296 (24): 2927–38. DOI:10.1001/jama.296.24.2927. PMID 17190893. Research Blogging.
  39. ↑ Delmas PD (July 2005). "The use of bisphosphonates in the treatment of osteoporosis". Current opinion in rheumatology 17 (4): 462–6. PMID 15956844. [e]
  40. ↑ McClung MR, Lewiecki EM, Cohen SB, et al (2006). "Denosumab in postmenopausal women with low bone mineral density". N. Engl. J. Med. 354 (8): 821–31. DOI:10.1056/NEJMoa044459. PMID 16495394. Research Blogging.
  41. ↑ Canalis E, Giustina A, Bilezikian JP (2007). "Mechanisms of anabolic therapies for osteoporosis". N. Engl. J. Med. 357 (9): 905–16. DOI:10.1056/NEJMra067395. PMID 17761594. Research Blogging.
  42. ↑ O'Donnell S, Cranney A, Wells GA, Adachi JD, Reginster JY (2006). "Strontium ranelate for preventing and treating postmenopausal osteoporosis". Cochrane Database Syst Rev (4): CD005326. DOI:10.1002/14651858.CD005326.pub3. PMID 17054253. Research Blogging.
  43. ↑ Marshall D, Johnell O, Wedel H (May 1996). "Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures". BMJ (Clinical research ed.) 312 (7041): 1254–9. PMID 8634613. PMC 2351094. [e]
  44. ↑ Bell, Katy J L; Andrew Hayen, Petra Macaskill, Les Irwig, Jonathan C Craig, Kristine Ensrud, Douglas C Bauer (2009-06-23). "Value of routine monitoring of bone mineral density after starting bisphosphonate treatment: secondary analysis of trial data". BMJ 338 (jun23_2): b2266. DOI:10.1136/bmj.b2266. Retrieved on 2009-06-24. Research Blogging.
  45. ↑ Johansson H, Kanis JA, Oden A, Johnell O, McCloskey E (March 2009). "BMD, clinical risk factors and their combination for hip fracture prevention". Osteoporos Int. DOI:10.1007/s00198-009-0845-x. PMID 19291344. Research Blogging.
  46. ↑ Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E (April 2008). "FRAX and the assessment of fracture probability in men and women from the UK". Osteoporos Int 19 (4): 385–97. DOI:10.1007/s00198-007-0543-5. PMID 18292978. PMC 2267485. Research Blogging.
  47. ↑ Anonymous (2007). Chronic rheumatic conditions. World Health Organization.
  48. ↑ Murphy, Kate. Splits Form Over How to Address Bone Loss, The New York Times, 2009-09-08. Retrieved on 2009-10-12.
  49. ↑ QFracture - authors response Hippisley-Cox J,Coupland C. BMJ 2011
  50. ↑ Ensrud KE, Lui LY, Taylor BC, Schousboe JT, Donaldson MG, Fink HA et al. (2009). "A comparison of prediction models for fractures in older women: is more better?". Arch Intern Med 169 (22): 2087-94. DOI:10.1001/archinternmed.2009.404. PMID 20008691. Research Blogging.
  51. ↑ Hippisley-Cox J, Coupland C (2009). "Predicting risk of osteoporotic fracture in men and women in England and Wales: prospective derivation and validation of QFractureScores.". BMJ 339: b4229. DOI:10.1136/bmj.b4229. PMID 19926696. Research Blogging.
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