Bisphosphonates in prostate carcinoma.

Adami S - Cancer - 1997 Oct 15; 80(8 Suppl): 1674-9
From NIH/NLM MEDLINE, HealthSTAR
NLM Citation ID:
98026758
Full Source Title:
Cancer
Publication Type:
Journal Article; Review; Review, Tutorial
Language:
English
Author Affiliation:
Department of Rheumatology, Ospedale di Valeggio, University of Verona,
Italy.
Authors:
Adami S
Number of References:
48
Abstract:
The majority of the patients with advanced prostate carcinoma have painful
skeletal metastases, which are responsible for significant skeletal
morbidity and disability. Most of these metastases are osteosclerotic, but
it has been shown that the abnormal osteoblastic bone formation within
metastases is preceded by osteoclastic activation, which appears to be
associated with bone pain. This provides the rationale for using
bisphosphonates, which are powerful and selective inhibitors of osteoclastic
bone resorption. Several bisphosphonates have been shown to be clinically
useful for the treatment of several conditions characterized by abnormal
osteoclastic bone resorption, including Paget's disease, primary
hyperparathyroidism, myelomatosis, and skeletal metastases. Its efficacy in
relieving pain in patients with skeletal metastases due to prostate
carcinoma has been confirmed in a few studies. The bisphosphonate clodronate
was extensively investigated in the study unit. When infused intravenously
i.v. (300 mg/day) relief of bone pain become appreciable within 3 days,
sometimes preceded by a transient pain flare. These clinical results are
very consistent and the residual pain usually is of extraosseous origin.
Thus, with regard to pain of strictly bone origin, unresponsive patients are
quite rare. Oral administration also is effective, but due to its limited
intestinal absorption the effective dose is on the order of 1600-3200
mg/day. These doses usually are well tolerated, but they may be a problem
for severely ill patients. Furthermore, the efficacy of treatment becomes
apparent only after a few days. Thus, oral clodronate usually is adopted as
a continuation of an i.v. course. The duration of the i.v. therapy should be
individualized, but usually the more prolonged the treatment the longer the
duration of the effect. For practical reasons, clodronate is infused daily
for 5 days (Monday-Friday) and the treatment course is repeated at the time
of any significant recurrence. The oral continuation prevents or delays the
recurrence of bone pain in most patients, but in some patients this therapy
has to be integrated occasionally with i.v. infusion. The duration of the
effect for the same bioavailable dose is somewhat related to the degree of
malignancy of the primary tumor. In an uncontrolled study, the author also
evaluated the effectiveness of alendronate given either i.v. or orally. A
single infusion of 5 mg alendronate i.v. produces roughly the symptomatic
effect of 5 i.v. infusions of 300 mg clodronate. Alendronate, 40 mg
orally/day, was effective in reducing bone pain in 11 of 12 patients with
bone metastases due to prostate carcinoma but who were not confined to bed.
In some patients with prostate carcinoma and a diffuse metastatic invasion
of the skeleton, there is indirect biochemical and histologic evidence of
osteomalacia. This can be aggravated by bisphosphonate administration
because of the transient striking prevalence of osteoblastic activity over
bone resorption, which also occasionally causes the appearance of
symptomatic hypocalcemia. Therefore, the use of large oral supplements of
calcium is recommended, particularly at the start of therapy. It is
conceivable that these calcium supplements also may be able to improve the
final clinical outcome of the bisphosphonate therapy. In conclusion,
administration of large doses of bisphosphonates is one of the most
cost-effective palliation treatments for patients with prostate carcinoma
with bone metastases, both as first-line therapy and in the long term. With
appropriate doses, a large proportion of patients can be maintained free of
bone pain until death. Studies of the ability of lower doses to prevent
skeletal morbidity in patients without metastases or with asymptomatic bone
lesions are warranted.


Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.