Osteoporosis

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LogoKeyPointsBox.pngIn the near future BMD will be deprecated in primary prevention relative to absolute fracture risk, measured over 10 (or possibly 5) years.

Osteoporosis describes reduced bone density due to loss of bone mass and increased bone porosity. It is distinguished from osteomalacia, where the amount of bone tissue is normal, but bone mineral content is reduced. It is defined as "a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture."[1]. The WHO study group in 1994 developed diagnostic criteria [2] for Dual energy X-Ray absorptiometry (DEXA,DXA) which remain the gold standard diagnostic criteria in use today

  1. Normal: BMD (bone mineral density) or BMC (bone mineral content) not more than 1 SD below the young adult mean (T-score above -1).
  2. Low bone mass (Osteopenia): BMD or BMC between 1 and 2.5 SD below young adult mean (T-score between -1 and -2.5).
  3. Osteoporosis: BMD or BMC 2.5 SD or more below the young adult mean (T-score at or below -2.5).
  4. Severe osteoporosis (or established osteoporosis): BMD or BMC 2.5 SD or more below the young adult mean in the presence of one or more fragility fractures.

The term Osteopenia has been deprecated recently by the ISCD relative to "Low Bone Mass".

Contents

Importance

Age-related fractures are a major health problem for both the individual concerned and society. Osteoporosis is the major present treatable condition where treatment reduces the incidence of these fractures. This may lead to the popular perception of osteoporosis being the problem, aided by good marketing techniques, rather than fracture burden, which can be reduced by accurate diagnosis and treatment of co-morbidities and multi-faceted, targetted falls interventions. While hip fracture is an obvious problem, it is apparent that the morbidity and economic burden of vertebral fractures has been depreciated due to these burdens being spread out over time, with indirect comorbidities.

European data Hip # Vertebral # Wrist #
Female life time risk 14% 29% 13%
Relative survival at 5 years 0.83 0.82 1.0
Health and social cost/fracture (Sweden 2005)[3] €14,000 €2000 €12,500

Absolute (Hip) Fracture Risk

  • Age
  • Sex
  • Steroid exposure (important)
  • Family history of hip fracture (important)
  • Prior fracture
  • Smoking
  • Alcohol intake > 2 units/day
  • Associated disease eg Rheumatoid arthritis
    • BMI...this is not an independent variable but is relatively easy to measure

The hip fracture algorithm score ( QFractureScores) is found on the QFracture web site. It is better than the FRAX algorithm[4].

The main problem holding back use of absolute fracture risk is that the T score is the gold standard for a treatment efficacy surrogate. The FRISK score predictes 75% of fractures in an Australian female population.

History

The term was first coined to describe bone appearance about 1850. Fuller Albright in 1941 first correlated postmenopausal osteoporosis with fracture risk. He had defined it as "a condition in which there is lack of bone tissue, but that tissue which remains is fully calcified"[5]. Examination of skeletons from multiple historic sites in Europe suggests osteoporosis has always been present in European populations.

Aetiology

Complex, but mainly environmental. Once corrected for socio-economic factors (which can cause a marked variation in fracture incidence/osteoporosis with in countries there is a marked correlation with latitude. In Europe the French (lowest) female rate of hip fracture is the same as the Norwegian (highest) male rate with an order of magnitude gradient from the Mediterranean to Norway. There is a low incidence in Africa, but race is not that protective relative to geography, with marked generational immigration effects. There is a correlation with Vitamin D status and in some populations various phenotypes of proteins associated with bone turn over.

Osteoporosis can also be caused by long-term use of anticonvulsants [1].

Genetic associations

Bone mineral density heritability is fairly strong but accounts for just over 3% of variation in bone mineral density. Multiple weak associations of a large number of genes have been reported including in alphabetical order:[6] [7] [8] [9] [10] [11] [12]

There are also associations with fracture risk with theses genes but perhaps not at identical points in the genome.

Therapeutic associations

Symptoms

Often asymptomatic until patients suffer a fracture. Common sites of fracture:

Investigations

  • DEXA(DXA) scan = Dual energy x-ray absorptiometry.
    • Lumbar spine - best for serial measurement/longitudinal follow up (as changes more...ie more senstive to change)
    • Total hip - best for hip # prediction (Should use IIHANES III standard)
    • T score is defined relative to fit young adult and is gold standard for diagnosis (see above WHO definition)
    • Z score is corrected for age, and is actually more useful than T score in children, premenopausal woman, men less than 50 years old.
    • Because of intrainstrument variability, do longitudinal studies on the same scanner
    • Radiation dose involved is very low, about a fifth of average annual exposure for an adult.
  • Others (Do not use T scores- QCT -2.5T cut off in caucasians at age 60 !, Calcaneal U/S cut off at age 120 odd !)
    • Calcaneal U/S - screening tool of questionable utility
    • Qualitative CT - main advantage is that it can distinguish cortical and trabecular bone denisity and more sensitive than DEXA.
    • These are not first line techniques

Treatment

Primary prevention vs secondary prevention

LogoKeyPointsBox.png
  • Bisphosphonates are present first choice and work well if good compliance
  • The evidence base for > 1200mg calcium or calcium in combination with >800 IU Vitamin D supplimentation is strong in those over 50.[13]
  • Bisphosphonates - first line (note 70% reduction in # if given when patients on long term steroids)
  • Calcium - if not calcium replete, institutionalised elderly (12% all fracture reduction [16])
    • Currently the issue of cardiovascular risk with calcium supplementation needs further study [17]
  • Vitamin D -institutionalised elderly
  • Denosumab - second line - patients must be vitamin D replete and some monitoring often indicated for hypocalcaemia
  • Strontium - third line as multiple contraindications and side- effects such as increased risk VTE
  • Specialist drugs
  • Specialist surgery

References

  1. Consensus Development Conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993;94:646-650.
  2. WHO Study Group on assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: Report of a WHO Study Group. WHO Technical Report Series 843; 1994.
  3. Borgstrom F, Zethraeus N, Johnell O, Lidgren L, Ponzer S, Svensson O, Abdon P, Ornstein E, Lunsjo K, Thorngren KG, Sernbo I, Rehnberg C, Jonsson B. Costs and quality of life associated with osteoporosis-related fractures in Sweden. Osteoporos Int. 2005;:1-14
  4. Hippisley-Cox J, Coupland C. Predicting risk of osteoporotic fracture in men and women in England and Wales: prospective derivation and validation of QFractureScores BMJ 2009;339:b4229
  5. Albright FA. Postmenopausal osteoporosis. JAMA 1941;116:2465-74
  6. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Center JR, Nguyen TV, Bagger Y, Gulcher JR, Eisman JA, Christiansen C, Sigurdsson G, Kong A, Thorsteinsdottir U, Stefansson K. Multiple Genetic Loci for Bone Mineral Density and Fractures. The New England journal of medicine. 2008 Apr 29.(Epub ahead of print) (Link to article – subscription may be required.)
  7. Lazáry A, Kósa JP, Tóbiás B, Lazáry J, Balla B, Bácsi K, Takács I, Nagy Z, Mezo T, Speer G, Lakatos P. Single nucleotide polymorphisms in new candidate genes are associated with bone mineral density and fracture risk. European journal of endocrinology / European Federation of Endocrine Societies. 2008 Aug; 159(2):187-96.(Link to article – subscription may be required.)
  8. Mullin BH, Prince RL, Dick IM, Hart DJ, Spector TD, Dudbridge F, Wilson SG. Identification of a role for the ARHGEF3 gene in postmenopausal osteoporosis. American journal of human genetics. 2008 Jun; 82(6):1262-9.(Link to article – subscription may be required.)
  9. Mencej S, Albagha OM, Prezelj J, Kocjan T, Marc J. Tumour necrosis factor superfamily member 11 gene promoter polymorphisms modulate promoter activity and influence bone mineral density in postmenopausal women with osteoporosis. Journal of molecular endocrinology. 2008 Jun; 40(6):273-9.(Link to article – subscription may be required.)
  10. Zhang H, Sol-Church K, Rydbeck H, Stabley D, Spotila LD, Devoto M. High resolution linkage and linkage disequilibrium analyses of chromosome 1p36 SNPs identify new positional candidate genes for low bone mineral density. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2008 Jul 3.(Epub ahead of print) (Link to article – subscription may be required.)
  11. Selezneva LI, Khusainova RI, Nurlygaianov RZ, Fazlyeva EA, Usenko KP, Lesniak OM, Khucnutdinova EK. Association of polymorphisms and haplotypes in the 5' region of COLIA1 gene with the risk of osteoporotic fractures in Russian women from Volga-Ural region. Genetika. 2008 Feb; 44(2):219-25.
  12. Liu YZ, Wilson SG, Wang L, Liu XG, Guo YF, Li J, Yan H, Deloukas P, Soranzo N, Chinnapen-Horsley U, Cervino A, Williams FM, Xiong DH, Zhang YP, Jin TB, Levy S, Papasian CJ, Drees BM, Hamilton JJ, Recker RR, Spector TD, Deng HW. Identification of PLCL1 gene for hip bone size variation in females in a genome-wide association study. PLoS ONE. 2008; 3(9):e3160.(Epub) (Link to article – subscription may be required.)
  13. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet. 2007 Aug 25; 370(9588):657-66.(Link to article – subscription may be required.)
  14. Lyles KW, Colón-Emeric CS, Magaziner JS et al. Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture NEJM 2007 10.1056/NEJMoa074941
  15. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. The New England journal of medicine. 2007 May 3; 356(18):1809-22.(Link to article – subscription may be required.)
  16. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet. 2007 Aug 25; 370(9588):657-66.(Link to article – subscription may be required.)
  17. Bolland MJ, Barber PA, Doughty RN, Mason B, Horne A, Ames R, Gamble GD, Grey A, Reid IR. Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial. BMJ, doi:10.1136/bmj.39440.525752.BE (published 15 January 2008 accessed 16 January 2008)
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