HIV related AVN (Avascular Necrosis) - Bone Death

Idiopathic osteonecrosis, hypofibrinolysis, high plasminogen activator
inhibitor, high lipoprotein(a), and therapy with Stanozolol.
Am J Hematol 1995 Apr;48(4):213-20 (ISSN: 0361-8609)
Glueck CJ; Freiberg R; Glueck HI; Tracy T; Stroop D; Wang Y
Cholesterol Center Jewish Hospital, Cincinnati, OH 45229, USA.
In five patients with idiopathic osteonecrosis (ON) of the hip, four having
hypofibrinolysis mediated by high plasminogen activator inhibitor (PAI-Fx),
and one with high Lp(a), our specific aim was to determine whether therapy
(Rx) with the anabolic-androgenic steroid, Stanozolol (6 mg/day), would
normalize PAI-Fx and Lp(a) and thus potentially ameliorate ON. Prior to Rx,
none of the four patients with high PAI-Fx could normally elevate tissue
plasminogen activator (tPA-Fx) after 10 min venous occlusion at 100 mm Hg.
After 12-18 weeks on Rx, PAI-Fx and stimulated tPA-Fx normalized in all four
patients. Prior to Rx, mean (SD) stimulated tPA-Fx was low, 0.4 +/- 0.3
IU/ml (lower limit of normal 2.28 IU/ml). On Rx, stimulated tPA-Fx
normalized, rising to 2.83 +/- 1.9 IU/ml, P = .004. Prior to Rx, mean (SD)
basal PAI-Fx was high, 99 +/- 68 (upper limit of normal 26.9 U/ml), and fell
on Rx to 22.5 +/- 22, P = .004. In two of the five patients normalization of
hypofibrinolysis or high Lp(a) was accompanied by major symptomatic
improvement. Prior to Rx, and 2 years after onset of unilateral hip pain,
one of the four patients with high PAI-Fx and low stimulated tPA-Fx could
walk only one block painfully. After 8 weeks on Stanozolol Rx, and
continuing through 54 weeks on Rx, he walked 2 miles per day without pain,
despite radiographic progression of ON. In three of the four patients with
high PAI and with osteonecrosis present 0.3, 2, and 6 years prior to
Stanozolol Rx, there was no clinical improvement after 14-156 weeks of Rx
despite normalization of stimulated tPA-Fx and PAI-Fx. The fifth patient, 1
month after onset of disabling hip pain, had normal PAI-Fx but high Lp(a)
(27 mg/dl), and MRI evidence of bone marrow edema ("transient
osteoporosis").
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A preliminary pilot study of treatment of thrombophilia and hypofibrinolysis
and amelioration of the pain of osteonecrosis of the jaws [see comments]
Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998 Jan;85(1):64-73
(ISSN: 1079-2104)
Glueck CJ; McMahon RE; Bouquot JE; Tracy T; Sieve-Smith L; Wang P
Cincinnati Jewish Hospital, Cholesterol Center, Ohio, USA.
OBJECTIVES: In a preliminary pilot study of 30 treatments in 26 patients
with osteonecrosis of the jaws and chronic disabling facial pain, our
specific aim was to determine whether, to what degree, and how safely
therapy of hypofibrinolysis and thrombophilia would ameliorate the chronic
pain associated with osteonecrosis of the mandible and maxilla. STUDY
DESIGN: Thrombophilia was treated with Coumadin (DuPont) in 10 patients;
hypofibrinolysis was treated with Winstrol (Sanofi-Winthrop) in 20 patients,
including 4 who had mixed thrombophilia and hypofibrinolysis and had
previously been treated with Coumadin. The initial treatment period was
targeted to be 4 months. Each patient was asked to keep a daily written
pain-relief numeric rating score and side-effects diary and to provide a
summary pain-relief numeric rating score and side effects compilation for
the total treatment period. RESULTS: There were 4 men and 22 women in the
study group; their mean age was 49 +/- 11 years. The mean onset of their
osteonecrosis pain was at age 45 +/- 12 years, and the mean duration of
their facial pain prior to therapy was 4.5 +/- 4.2 years. Ten patients had
one or more thrombophilic traits (there were two patients with protein C
deficiency, five with resistance to activated protein C and/or the mutant
Factor V Leiden gene, and four with high anticardiolipin antibodies). The 10
patients who were thrombophilic were treated with Coumadin (the
international normalized ratio was targeted to 2.5-3.0) for 22 +/- 9 weeks.
By self-reported pain-relief numeric rating scores, 6 of the 10 patients
with thrombophilia (60%) had > or = 40% pain relief, 2 (20%) had no change,
and 2 (20%) had increased pain (30% and 80% worse). Nine of the 10 patients
with thrombophilia (90%) had no Coumadin-related side effects; 1 patient
(10%) stopped Coumadin therapy (after 28 weeks) because of nosebleeds.
Winstrol (6 mg per day) was used for 16 +/- 9 weeks in 20 patients with
hypofibrinolysis, some of whom had one or more hypofibrinolytic traits (10
had high levels of plasminogen activator/inhibitor activity, usually
accompanied by low stimulated tissue plasminogen activator activity; 13 had
high Lp[a] lipoprotein). Of these 20 patients with hypofibrinolysis, 9
patients (45%) had > or = 40% pain relief, 3 patients (15%) had 20% to 30%
relief, 5 patients (25%) had no improvement, and 3 patients (15%) had
increased pain (30% worse, 60% worse, and 70% worse). Six of the 20 patients
with hypofibrinolysis (30%) had no Winstrol-related side effects, while 14
(70%) had side effects that could be attributed to Winstrol, including
weight gain, peripheral edema, increased facial and body hair, and acne--all
of which were reversed within 6 weeks of stopping Winstrol therapy.
CONCLUSIONS: We postulate that thrombophilia and hypofibrinolysis lead to
impaired venous circulation and venous hypertension of the mandible/maxilla
with subsequent development of osteonecrosis and chronic facial pain. In
many patients, facial pain can be ameliorated by treating the pathogenetic
coagulation defects with Coumadin or Winstrol. Large, double-blind,
placebo-controlled crossover studies will be required in the future to
validate these preliminary results and to determine whether pain relief with
Coumadin or Winstrol justifies the risks and side effects associated with
these medications, especially for long-term use, in osteonecrosis of the
jaws.
Comment in: Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998 Jul;
86(1):3-7
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Stanozolol stimulates remodelling of trabecular bone and net formation of
bone at the endocortical surface.
Clin Sci (Colch) 1991 Oct;81(4):543-9 (ISSN: 0143-5221)
Beneton MN; Yates AJ; Rogers S; McCloskey EV; Kanis JA
Department of Human Metabolism, University of Sheffield Medical School, U.K.
1. We studied the mechanism of action of the anabolic steroid, stanozolol,
in 23 patients with osteoporosis, using a combination of biochemical and
histomorphometric techniques. 2. Treatment with stanozolol (5 mg/day) for 1
year was associated with a marked and significant decrease in the fasting
urinary excretion of calcium (P less than 0.01) but not with changes in the
serum concentrations of calcium and phosphate, the serum activity of
alkaline phosphatase, the renal tubular reabsorption of calcium or the
urinary excretion of hydroxyproline. 3. Histological examination of
trabecular bone showed an increase in bone turnover and the bone formation
rate increased twofold (P less than 0.02). There were no significant changes
in bone volume or wall thickness after treatment. Tetracycline labelling was
used to discriminate bone structural units completed before and during
treatment. Measurements of the wall thickness of those bone structural units
formed during treatment showed no significant change. 4. Measurements made
on the endocortical surface also showed an increase in bone turnover, but in
contrast to trabecular bone, the bone structural units formed at
endocortical sites during treatment had a significantly greater wall
thickness than those formed before treatment (P less than 0.05). 5. We
conclude that stanozolol increases the turnover of trabecular bone and
increases the endocortical apposition of bone.

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