Osteoporosis

From Ganfyd

In 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".

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.

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]}

• ARHGEF3 gene which codes for components of the the RhoGTPase-RhoGEF pathway
• COLIA1 gene (codes for type 1 collagen)
• ESR1 gene (codes for estrogen receptor 1 ) and its regulator area
• FABP3 gene (codes for fatty acid-binding protein-3)
• FGFR1 gene (codes for fibroblast growth factor receptor-1)
• LRP5 gene (odes for LDL-receptor-regulated protein 5)
• OPG gene (codes for osteoprotegerin, a major regulator of osteoclast activity and bone resorption)
• PLCL1 gene (codes for phospholipase c-like 1)
• TIMP2 gene (codes for tissue inhibitor of metalloproteases-2)
• TNFSF11 gene (codes for RANKL a major regulator of osteoclast activity and bone resorption)
• An area on 1.36 near ZBTB40 and WNT4 genes, but also including RERE, G1P2, SSU72 and CCDC27 candidate genes
• Possibly in HLA complex at 6p21

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

Therapeutic associations

• Bed rest
• Corticosteroids
  • Oral, parenteral and high doses of inhaled corticosteroids (>800 µg/day of ]beclometasone or equivalent, in adults)
  • Greatest rate of bone loss in first 6-12 months of use
  • Cumulative dose association
    • Thus use proven preventive measures early when steroids commenced but never to late
• Anticonvulsants
  • Related to increased metabolism of vitamin D with phenytoin, carbamazepine and phenobarbitone
  • Absence of evidence for some drugs such as valproate and lamotrigine
• Glitazones(thiazolidinediones)
  • • Activation of the peroxisome proliferator-activated receptor (PPAR-&gamma) increases bone marrow adiposity and decreases osteoblastogenesis
  • Proton pump inhibitors
    • Association with higher doses and longer duration of use
    • Mechanism possibly due to decreased absorption of calcium when hypochlorhydria.
      • Theoretically calcium supplementation would work and any drug or condition reducing stomach acidity could cause this risk
• Aromatase inhibitors
• GnRH agonists
• Possible (unproven)
  • selective serotonin reuptake inhibitors
  • antiretroviral therapy

Symptoms

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

• Distal wrist fractures
• Vertebral crush/collapse fractures
• Neck of femur fractures

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

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)
  • Zoledronic acid given with vitamin D reduces mortality after fractured neck of femur by over 3% at 3 years^[14] and has the most impressive reduction in fracture rate data^[15], although it may not be the most cost effective option in orally compliant patients.
• 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
• Strontium - second line
• Specialist drugs
  • Teriparatide (use limited by cost)
  • Calcitonin (use limited by nausea and cost)
• Specialist surgery
  • Kyphoplasty-for fresh painful/symptomatic vertebral fractures - needs MRI selection

References