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Analysis Too Much Medicine

Overdiagnosis of bone fragility in the quest to prevent hip fracture

BMJ 2015; 350 doi: (Published 26 May 2015) Cite this as: BMJ 2015;350:h2088

Re: Overdiagnosis of bone fragility in the quest to prevent hip fracture- before we reach breaking point

Dear Sir

Further to the recent publication on over-prediction of hip fracture risk and ensuing challenges (1), current data highlight the limitations of Dual-Energy-X-ray-Absorptiometry scans (DEXA). In this context, at best, DEXA scans (which measure bone mineral density (BMD)) can account for no greater than 50% of overall bone strength (defined as the ability to resist fracture). This is because the resulting images are two-dimensional (2D) and therefore unable to capture skeletal micro-architecture, which also contributes to bone strength (2).

Clearly, better clinical measures of overall bone strength that more accurately reflect the ability of that bone to resist fracture represent an unmet need and are urgently required. Recent evidence suggests that micro-Computed Tomography (CT) scans, which enable 3D imaging, might provide a solution but use so far has necessarily been limited to ex vivo assessment owing to radiation hazards as well as technical and accessibility issues (3, 4). However micro-CT images have identified bone volume fraction (BVF, the volumetric distribution of bone mass) as a strong determinant of bone strength (r2 > 0.8) (5,6).

Other potential tools, alone or in combination with imaging may also play a role. For example serum biomarkers of bone metabolism (7,8) along with other imaging modalities such as magnetic resonance imaging could capture the complex factors that make up bone strength (9). Input of such data into pre-existing algorithms like the FRAX (a Fracture Risk Assessment tool calculator) (10) might help reduce the over-prediction issue currently faced.

Clinical trials of medications for non-bone disease, that nonetheless may also have the unwanted effect of inducing rapid changes to bone strength, could offer opportunities for accelerating the assessment of currently developing fracture prediction tools. An example is a sub-study of PATCH, (Prostate Adenocarcinoma TransCutaneous Hormones (MRC PR09)), an ongoing National Phase III randomized clinical trial ( number NCT00303784) comparing efficacy and toxicity of LHRHa (lutenising hormone releasing hormone analogues) and oestradiol transdermal patches in suppressing testosterone to castrate levels (androgen deprivation therapy (ADT)). LHRHa delivers this through suppression of (initially) testosterone (by about 95%), and then oestradiol (by about 80%; oestradiol is synthesized in men from testeosterone through aromatase). Lack of these sex hormones rapidly alters the balance of activity between osteoblasts and osteoclasts resulting in a loss of up to 10% BMD in the first year of ADT and 2-4% annually thereafter (11) and so development of osteoporosis. Conversely, whilst transdermal oestradiol patches (EP) also lead to suppression of testosterone, the ‘lost’ endogenous oestradiol is replaced by the exogenous oestradiol patches, resulting overall in a gain of BMD (12,13).

In light of the above and the pressing need to resolve the problems identified by Järvinen et al, it would appear prudent to invest in further studies to determine the extent and management of this issue now, before the NHS itself becomes fractured, having reached a breaking point in the face of an ever-ageing population.

1. Järvinen TL. Overdiagnosis of bone fragility in the quest to prevent
hip fracture. BMJ. 2015. 2015;350:h2088
2. Greenspan SL, Wagner J, Nelson JB, Perera S, Britton C, Resnick NM. Vertebral fractures and trabecular microstructure in men with prostate cancer on androgen deprivation therapy. J Bone Miner Res. 2013;28:325–32.
3. Genant HK, Engelke K, Prevrhal S. Advanced CT bone imaging in osteoporosis. Rheumatology. 2008;47:suppl 4:9-16
4. Cooper D, Turinsky A, Sensen C, Hallgrimsson B. Effect of voxel size on 3D micro-CT analysis of cortical bone porosity. Calcified Tissue Int. 2007;80(3):211-9.
5. Nazarian A, von Stechow D, Zurakowski D, Muller R, Snyder BD. Bone volume fraction explains the variation in strength and stiffness of cancellous bone affected by metastatic cancer and osteoporosis. Calcified Tissue Int. 2008;83(6):368-79.
6. Van Hemelrijck M, Garmo H, Michaelsson K, Thorstenson A, Akre O, Stattin P, et al. Mortality following hip fracture in men with prostate cancer. PloS one. 2013;8(9):e74492.
7. Wilson HCP, Shah SIA, Abel, PD, Price P, Honeyfield L,Edwards S, Abel RL. Contemporary hormone therapy with LHRH agonists for prostate cancer: avoiding osteoporosis and fracture. Central European Journal of Urology. 2015 (In press)
8. Dabaja A, Bryson C, Schlegel P, Paduch D. The effect of hypogonadism and testosterone-enhancing therapy on alkaline-phosphatase and bone mineral density. BJU Int 2015; 115: 3
9. Kröger H, Vainio P, Nieminen J, Kotaniemi A. Comparison of different models for interpreting bone mineral density measurements using DXA and MRI technology. Bone.1995. 17: 157-5
11. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer.NEJM. 2005;352(2):154-64
12. Langley RE, Cafferty FH, Alhasso AA, et al. Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09). The Lancet Oncology 2013;14:306-16
13. Langley, R.E., Duong T., Jovic G. et al., Bone density in men receiving androgen deprivation therapy for prostate cancer: a randomized comparison between transdermal estrogen and luteinising hormone-releasing hormone agonists. Journal of Clinical Oncology. 2014, 32, suppl; abstr 5067

Competing interests: No competing interests

05 June 2015
Hannah CP Wilson
Post-graduate Medical Student
Dr Imran Shah, Prof Paul Abel, Prof Pat Price, Dr Richard Abel
Imperial College London
Charing Cross hospital, Fulham Palace Road, London W6 8RF