Sunday, May 6, 2012

Mechanisms of Osteoporosis: Part 1


The signals involved in the inflammatory response promote bone loss.  The receptor activator for NF-κB ligand (RANKL) is essential for osteoclastogenesis and NF-κB is one of the key pro-inflammatory cytokines.  Various other pro-inflammatory cytokines (such as IL-1, IL-6, TNF-α, M-CSF) and prostaglandin E2 (PGE2) increase osteoclast synthesis and activity and induce osteoblast apoptosis, leading to a higher rate of bone resorption and a lower rate of bone formation [1] [2]. 

Evidence to support the role of inflammation in osteoporosis: 
  • Markers of oxidative stress [5] and inflammation (IL-6 [3] and CRP [4]) are strongly associated with lower bone mineral density
  • Periodontitis is associated with osteoporosis and LPS increases bone resorption and bone mineral density loss [6]
  • Osteoporosis is associated with bacterial infections and markers of chronic infection, such as CRP [7]
  • Osteoporosis is associated with many inflammatory diseases such as liver cirrhosis [8], rheumatoid arthritis, coeliac disease, lupus, inflammatory bowel disease [9] and cardiovascular disease [10]
  • Two common risk factors for osteoporosis are smoking (RR 1.25 or 4.9 if low vitamin C and E) [11]) and drinking (> 2 standard drinks RR 1.23) [12].  Both increase oxidative stress and inflammation [13] [14].
  • Bone mineral density declines with age and inflammation increases with age [15]
  • Conjugated linoleic acid and long chain omega 3s (EPA+DHA) seem to increase bone mineral density by decreasing pro-inflammatory cytokines and PGE2 [16] [17] [18] 

Overall, estrogen* and testosterone inhibit osteoblast apoptosis promote osteoclast apoptosis and reduces osteoclast activity.  Estrogen or testosterone deficiency results in rapid bone loss.  Estrogen also has anti-inflammatory and antioxidant effects.  It reduces the pro-inflammatory cytokines mentioned above [19], increases glutathione peroxidase (the antioxidant enzyme for hydrogen peroxide) [20] and increases osteoprotegerin, which inhibits the effects of NF-κB by acting as a decoy receptor for RANKL [19]. 

Menopause causes a reduction in estrogen, which leads to elevated hydrogen peroxide and pro-inflammatory cytokines, which may explains the rapid bone loss during menopause [1] [21].  After menopause bone loss is not quite so rapid, but leaves postmenopausal women at greater risk compared to men. 

Homocystinuria is a rare genetic disease with high levels of homocysteine and early-onset osteoporosis.  Homocysteine is an inflammatory substance that is associated with lower bone mineral density, higher rates of bone loss and higher fracture risk (RR 1.4 [22] and 2.0-2.2 [23]).  Vitamin B6, B9 (folate), B12 and choline are needed to metabolise homocysteine and low vitamin B12 and B6 are associated with low bone mineral density and low bone strength respectively (after adjusting for other micronutrient intake) [11].  Mega doses of folate and vitamin B12 reduced fracture rates by 50% following a stroke** [24] 

Some inflammatory diseases are treated with glucocorticoids* (such as cortisone) to reduce inflammation.  This further increases the risk of osteoporosis as glucocorticoids increase osteocyte apoptosis and fracture rates by 55-418% depending on the dose ** [25] [26] 

* Estrogen also inhibits sclerostin [27] 

** There was no significant difference in bone mineral density as homocysteine acts on the collagen crosslinks and bone strength 

*** The effects of glucocorticoids might suggest a possible link between stress/anxiety and osteoporosis.  Depression is associated with an increased risk of osteoporosis [28], but depression is also an inflammatory disease, there are other confounders with depression.

**** People taking glucocorticoids who have fractures tend to have higher bone mineral density than people with age-related osteoporosis, which suggests glucocorticoids act on osteocytes rather than bone formation/resorption. 

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