Inflammation
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]
** 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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