Effects of diphosphonates in disorders of bone turnover.

This thesis describes several interrelated
studies concerning the effects of diphosphonates in the
treatment of disorders of bone turnover.
Diphosphonates have previously been shown to
suppress bone turnover in Paget's disease when given
orally for at least three months. However, five daily
intravenous infusions of the diphosphonates, clodronate,
etidronate and a newer agent, aminohexane diphosphonate
(AHDP), induced marked and sustained biochemical and
clinical changes similar to those achieved with long-term
oral treatment. These new regimens may be useful in the
management of Paget's disease.
The assessment of biochemical response in
Paget's disease, particularly in re-treated patients, is
more complex than hitherto described. The pre-treatment
serum alkaline phosphatase and, in re-treated patients,
the extent of biochemical relapse are important
determinants of response.
Little was previously known of the effects of
high doses of diphosphonates on mineral metabolism.
Inhibition of mineralisation occurred following all 3
intravenous diphosphonates. However, this effect was
partial and short-lived following clodronate or AHDP, but
was complete and much more sustained following
etidronate. All three diphosphonates induced
hyperphosphataemia by increasing renal tubular
reabsorption of phosphate. This latter effect was
related, both temporally and quantitatively, to the
effects of these agents on skeletal mineralisation
suggesting a possible causal relationship.
Hypocalcaemic responses were consistently
observed in pagetic patients following intravenous
clodronate or AHDP, but not following etidronate.
Similarly, infusions of either clodronate or AHDP, but
not etidronate, induced normalisation of mean serum
calcium in patients with hypercalcaemia of malignancy.
Furthermore, oral clodronate, but neither high-dose nor
low-dose oral etidronate, induced significant
hypocalcaemic responses in patients with primary
hyperparathyroidism. The degree of inhibition of bone
resorption was similar for each of the diphosphonates in
all of the disorders studied, suggesting that the
attenuated hypocalcaemic effects of etidronate resulted
from the greater impairment of mineralisation that
occurred following treatment with this agent.