Bisphosphonates - Osteogenesis Imperfecta - page 451

CHAPTER

53

Bisphosphonates

Nick J. Bishop 1 and Graham Russell 2
1 University of Sheffield, Sheffield Children's Hospital, Western Bank, Sheffield, UK, 2 Oxford
University, Oxford, UK and University of Sheffield, Sheffield, UK

BISPHOSPHONATES

Once absorbed, the distribution of drug is primar-
ily into bone, but there is some soft tissue uptake into
liver, kidney and spleen. 12 There is some variation in
the uptake of drug within the skeleton as well; stud-
ies using radio-labeled zoledronate and other bisphos-
phonates suggest a higher concentration of drug in the
axial as opposed to appendicular skeleton after a single
dose. 12 Within a single bone, uptake is greatest in areas
where trabecular bone predominates. The higher intake
of bisphosphonate in areas of increased turnover/
remodeling forms the basis for technetium bone scans;
99m Tc is complexed with a simple bisphosphonate, such
as medronate. Studies using 99m Tc-labeled or other
labeled bisphosphonates indicate that within 24 hours
drug not bound to bone has either been excreted or is in
the extracellular matrix close to a bone surface. 13
The proportion of retained compound varies widely
between patients even after intravenous administration,
reflecting affinity for bone, differences in renal func-
tion, and the rate of bone turnover prior to treatment.
However, within-patient differences are small even
after prior treatment. 14 There does not appear to be a
clear relationship between retention and disease state -
similar variation of 10-90% in bisphosphonate retention
has been reported across a number of disorders includ-
ing metastatic bone disease, osteoporosis and Paget's
disease. Specific information regarding retention in
osteogenesis imperfecta (OI) is lacking.
It is thought that the drug once circulating in the
blood will bind to surfaces with a high crystalline cal-
cium content such as naked bone; the passage of drug
from the bloodstream to the bone surface is thought
to be passive and paracellular. 14 The key feature of
bisphosphonates which allows them to affect osteoclast
activity is the central P-C-P element; substitution of the

Bisphosphonates (originally called diphosphonates)
were first synthesized in the mid-19th century, but their
biological effects were not discovered until the 1960s,
and their first clinical uses took place in the 1970s. The
earliest described biological effects of bisphosphonates
were to inhibit vascular calcification,1 1 but their effects
on bone resorption 2 turned out to be more important
for their ultimate clinical success. 3
The simple structure of the initial compounds was
very similar to the endogenous mineralization inhibitor
pyrophosphate, with the geminal oxygen replaced with
a carbon atom that allows for two side chains desig-
nated R1 and R2. During the past 40 years or so, many
hundreds of bisphosphonates have been made, but
only a dozen or so have reached clinical development
( Figure 53.1 ). 4,5 The more recently synthesized potent
molecules all have a nitrogen atom within the R2 side
chain. The history, clinical uses and structure-activ-
ity relationships among bisphosphonates have been
reviewed in detail elsewhere. 6-9
Bisphosphonates can be administered orally or
intravenously. Following oral administration, bisphos-
phonates are absorbed throughout the gastrointestinal
tract, but primarily in the small intestine and stomach.
Absorption is paracellular - no active (or passive) tran-
scellular processes have been identified - and gener-
ally rather poor, typically around 0.7% for the most
commonly used nitrogen-containing compounds, and
slightly higher (2-4%) for some of the non-nitrogen
compounds. 10 Co-administration of anything other than
water serves to further reduce absorption; there is some
evidence that different formulations and coatings can
also affect uptake. 11