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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| pravastatin 80mg/d | Experimental | Oral administration of pravastatin at 1 h before zoledronic acid infusion, 24 h and 48 h after zoledronic acid infusion |
|
| placebo | Placebo Comparator | Oral administration of placebo at 1 h before zoledronic acid infusion, 24 h and 48 h after zoledronic acid infusion |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pravastatin Sodium 80 MG | Drug | daily oral administration of 80mg |
|
| 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 |
| 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. |
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Inclusion Criteria:
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.
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Qi Liu, Ph. D. | Contact | +8615501060136 | liuqicpu@hotmail.com |
| Name | Affiliation | Role |
|---|---|---|
| Chunli Song, M.D.; Ph. D. | Peking University Third Hospital | Principal Investigator |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23184667 | Background | Sieber P, Lardelli P, Kraenzlin CA, Kraenzlin ME, Meier C. Intravenous bisphosphonates for postmenopausal osteoporosis: safety profiles of zoledronic acid and ibandronate in clinical practice. Clin Drug Investig. 2013 Feb;33(2):117-22. doi: 10.1007/s40261-012-0041-1. | |
| 15606619 | Background | Hewitt RE, Lissina A, Green AE, Slay ES, Price DA, Sewell AK. The bisphosphonate acute phase response: rapid and copious production of proinflammatory cytokines by peripheral blood gd T cells in response to aminobisphosphonates is inhibited by statins. Clin Exp Immunol. 2005 Jan;139(1):101-11. doi: 10.1111/j.1365-2249.2005.02665.x. |
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| ID | Term |
|---|---|
| D015663 | Osteoporosis, Postmenopausal |
| D000210 | Acute-Phase Reaction |
| ID | Term |
|---|---|
| D010024 | Osteoporosis |
| D001851 | Bone Diseases, Metabolic |
| D001847 | Bone Diseases |
| D009140 | Musculoskeletal Diseases |
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| ID | Term |
|---|---|
| D017035 | Pravastatin |
| ID | Term |
|---|---|
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
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| Placebo | Drug | daily oral administration |
|
|
| 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 |
| 11465120 | Background | Sireci G, Espinosa E, Di Sano C, Dieli F, Fournie JJ, Salerno A. Differential activation of human gammadelta cells by nonpeptide phosphoantigens. Eur J Immunol. 2001 May;31(5):1628-35. doi: 10.1002/1521-4141(200105)31:53.0.CO;2-T. |
| 29055564 | Background | Schneiders FL, Huijts CM, Reijm M, Bontkes HJ, Verheul HMW, de Gruijl TD, van der Vliet HJ. The effects of systemic treatment with aminobisphosphonates and statins on circulating Vgamma9Vdelta2-T cells in patients with advanced cancer. Immunobiology. 2018 Feb;223(2):171-177. doi: 10.1016/j.imbio.2017.10.029. Epub 2017 Oct 16. |
| 35831045 | Derived | Liu Q, Han G, Li R, Fan D, Du G, Zhang M, Tao L, Li H, Liu D, Song C. Reduction effect of oral pravastatin on the acute phase response to intravenous zoledronic acid: protocol for a real-world prospective, placebo-controlled trial. BMJ Open. 2022 Jul 13;12(7):e060703. doi: 10.1136/bmjopen-2021-060703. |
| D008659 |
| Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D007249 | Inflammation |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |