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.