Pravastatin Reduces Acute Phase Response of Zoledronic Acid

Study Overview
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Brief Summary
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Acute phase response (APR) is one of the most common adverse events in osteoporosis with zoledronic acid treatment. It's reported that this reaction is related to the blockade of the mevalonate pathway, leading to isopentenyl pyrophosphate (IPP) accumulation. And the latter can active γδT cells in the circulation, resulting in inflammatory cytokine release. Statins can inhibit the conversion of HMG-CoA to mevalonate that may reduce the accumulation of IPP. Therefore, it is possible that statins can be taken in advance to reduce APR caused by zoledronic acid infusion.

Official Title
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The Reduction Effect of Oral Pravastatin on Acute Phase Response of Intravenous Zoledronic Acid: a Real-world Study

Conditions
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Postmenopausal Osteoporosis

Intervention / Treatment
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* Drug: Pravastatin Sodium 80 MG
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chinese Han ethnic postmenopausal women. Bone mineral density values of less than 2.5 standard deviations (SD) below the normal adult mean. Willing to participate in this study. Exclusion Criteria: Prior treatment with biphosphonates (oral or intravenous). Fever and/or any viral or bacterial infections within 30 days prior to randomization. Patients with evidence of any cancer or with a history of cancer. Contraindication to zoledronic acid: Known hypersensitivity to zoledronic acid or other bisphosphonate or zoledronic acid formulation (excipients); Serum calcium level < 2.13 mmol/L (8.5 mg/dL), free serum calcium level <0.95 mmol/L (3.8 mg/dL) or untreated hypocalcemia; Childbearing or child-breastfeeding women; Creatinine clearance < 35 mL/min; Restrictions: Patients currently receiving aminoglycoside, diuretics or thalidomide. Contraindication to pravastatin: Known hypersensitivity to pravastatin or other excipients in pravastatin sodium formulation. Restrictions: Patients with severe liver insufficiency, history of severe liver insufficiency, active liver disease or continuously elevated transaminase; Patients with severe renal insufficiency or history of severe renal insufficiency; Patients currently receiving fibrates (e.g., bezafibrate), immunosuppressive drug (e.g., cyclosporine) or niacin. Any physiological or medical condition which, in the opinion of the investigator, would preclude the participant from this trail.
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pravastatin 80mg/d<br>Oral administration of pravastatin at 1 h before zoledronic acid infusion, 24 h and 48 h after zoledronic acid infusion | Drug: Pravastatin Sodium 80 MG<br>* daily oral administration of 80mg<br>* Other names: Meibailezhen;|
| Placebo Comparator: placebo<br>Oral administration of placebo at 1 h before zoledronic acid infusion, 24 h and 48 h after zoledronic acid infusion | Drug: Placebo<br>* daily oral administration<br>* Other names: Meibailezhen placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of acute phase response | Effect of oral pravastatin on the incidence of acute phase response within 72 hours after zoledronic acid infusion | 0-72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence time of fever | Effect of oral pravastatin on the occurrence time of fever after zoledronic acid infusion | from 8:00 a.m. to 8:00 p.m. with interval of 4 hours in Day -2 and Day -1, from 9:00 a.m. to 9:00 p.m. with interval of 3 hours in Day 0, 1, 2, 3. It should be recorded when fever occurs in other time. | 
| Severity of fever | Effect of oral pravastatin on the severity of fever (body temperature) after zoledronic acid infusion. | from 8:00 a.m. to 8:00 p.m. with interval of 4 hours in Day -2 and Day -1, from 9:00 a.m. to 9:00 p.m. with interval of 3 hours in Day 0, 1, 2, 3. It should be recorded when fever occurs in other time. | 
| Occurrence time of pain | Effect of oral pravastatin on the occurrence time of pain after zoledronic acid infusion | from 8:00 a.m. to 8:00 p.m. with interval of 4 hours in Day -2 and Day -1, from 9:00 a.m. to 9:00 p.m. with interval of 3 hours in Day 0, 1, 2, 3. It should be recorded when pain occurs in other time. | 
| Severity of pain | Effect of oral pravastatin on the severity of pain (visual analogue scale, VAS) after zoledronic acid infusion | from 8:00 a.m. to 8:00 p.m. with interval of 4 hours in Day -2 and Day -1, from 9:00 a.m. to 9:00 p.m. with interval of 3 hours in Day 0, 1, 2, 3. It should be recorded when pain occurs in other time. | 
| Frequency of acetaminophen usage after zoledronic acid infusion | To compare the frequency of acetaminophen within 72 hours after zoledronic acid infusion between pravastatin arm and placebo arm. | within 72 hours after zoledronic acid infusion | 
| Amount of acetaminophen usage after zoledronic acid infusion | To compare the amount of acetaminophen within 72 hours after zoledronic acid infusion between pravastatin arm and placebo arm. | within 72 hours after zoledronic acid infusion | 
| White blood cells | To compare the changes in white blood cells (WBC) count within 48 hours after zoledronic acid infusion between pravastatin arm and placebo arm. | baseline and 48 hours after infusion | 
| C reaction protein | To compare the changes in C reaction protein (CRP) within 48 hours after zoledronic acid infusion between pravastatin arm and placebo arm. | baseline and 48 hours after infusion | 
| interferon-γ expression | To compare the changes in interferon-γ (IFN-γ) within 48 hours after zoledronic acid infusion between pravastatin arm and placebo arm. | baseline and 48 hours after infusion | 
| interleukin-6 expression | To compare the changes in interleukin-6 (IL-6) within 48 hours after zoledronic acid infusion between pravastatin arm and placebo arm. | baseline and 48 hours after infusion | 
| γδT cells activation | To compare the changes in count of γδT cells activation within 48 hours after zoledronic acid infusion pravastatin arm and placebo arm. | baseline and 48 hours after infusion | 
| Adverse event occurrence | The occurrence of adverse event within 10 days after zoledronic acid infusion | 0-10 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute phase response, zoledronic acid, pravastatin