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representing the number of standard deviations (SD) from the mean peak BMD (at age 20) for
that population (sex and ethnicity).

The relationship between BMD and risk of fracture is continuous, with an approximately two-
fold increase in risk with each SD decrease in BMD11. The World Health Organization has
defined thresholds for BMD: a T score of >-1 is regarded as normal, values between -1 and -
2.5 as osteopenic, and below -2.5 as osteoporotic7. Osteoporosis is considered
severe/established if non-traumatic fractures occur in this setting. Z scores are also sometimes
quoted, particularly for children, representing the number of SDs from age-matched population
controls.

Whilst relationship between BMD and fracture risk is clearly established, the use of BMD
alone to assess risk is not recommended. Although it has high specificity, the sensitivity is low
(approximately 50%)12, meaning that half of fractures will occur in patients said not to have
osteoporosis on this measure.

Vitamin D metabolism
The major biologically active metabolite of vitamin D is 1,25 dihydroxy vitamin D, which, in
addition to its roles in bone metabolism, has antiproliferative, prodifferentiation and
immunosuppressive effects. Severe vitamin D deficiency results in defective mineralisation
(osteomalacia, or rickets in the developing skeleton). Serum levels of 25-hydroxy vitamin D
are usually measured, and the lower limit of normal is commonly set at <20 nmol/L. It is
recognised that more subtle insufficiency, with levels up to 37.5 nmol/L, may be associated
with secondary hyperparathyroidism and increased bone turnover, and play a role in age-
related bone loss and osteoporosis13.

Dietary sources of vitamin D are limited, and in normal circumstances most is cutaneously
synthesised, which is sunlight dependent. Thus populations who are
housebound/institutionalised, or those who avoid sunlight for cultural reasons will by default
rely more on dietary sources, and be at risk of deficiency. Intestinal, liver, renal or
cardiopulmonary diseases are also risk factors due to secondary effects. Although frank
osteomalacia/rickets is relatively rare in Western societies, vitamin D insufficiency may be
very common, affecting 57% of medical inpatients in one US study14. Importantly, many of
these did not have known risk factors and thus would have been missed without screening.

Biochemical markers of bone turnover
In addition to assessing vitamin D levels, and traditional biochemical bone markers such as
calcium, phosphate, parathyroid hormone (PTH) and various other markers of bone turnover
can easily be detected in blood and urine with commercially available kits. The bone isoform
of serum alkaline phosphatase is the most commonly measured, but is relatively insensitive as
a screening test. There are several serum markers of bone formation including osteocalcin (a
non-collagenous matrix protein secreted by osteoblasts) and circulating peptides of type I
collagen. Similarly serum levels of peptides representing degraded products from osteoclastic
activity (e.g. N-telopeptide of type I collagen) can be used to assess bone resorption15. Skeletal
growth factors (e.g. insulin growth factor 1, IGF1) also play a role.

Bone turnover is increased during growth periods and fracture repair, and such markers have
been correlated with histology from bone biopsy in both health and disease16. Such markers
are increasingly cited in papers as indicators of metabolic bone disease17, but they have not
been validated against clinically meaningful endpoints in prospective studies and further
research is required before they can be used to detect at-risk individuals or monitor treatment.