Prednisolone

Limits on what this shows

• At-risk subgroups: Prolonged or high-dose therapy, postmenopausal women, pre-existing low bone mineral density.
• Counter-evidence: None found contradicting the direction; the companion Vitamin D entry below found no additional deficit versus disease controls, which bounds that separate vitamin but does not weaken the calcium-excretion finding, which was placebo-controlled within the same trial.

Regulatory status

DailyMed prednisolone label (Warnings): "all corticosteroids increase calcium excretion."

Population evidence

RCT, 48 healthy men, prednisolone 10 mg twice daily for 7 days: renal calcium excretion increased ~45%; serum PTH rose up to 18.5%; bone formation markers fell (osteocalcin −34.7%, PICP −25.9%); bone resorption marker ICTP fell −28.4% (Bone, 1998).

Mechanism

Named: decreased intestinal calcium absorption plus increased renal calcium excretion, triggering compensatory PTH rise and altered bone turnover (Holland-Frei Cancer Medicine, NCBI Bookshelf; confirmed directionally by the RCT above).

Functional marker

Serum PTH rose (not fell or stayed flat) in the RCT, satisfying the requirement that an unfalsifiable "levels stay normal but tissue is depleted" claim be checked against a validated functional marker that actually moved.

Counter-evidence held on record

This is a real, mechanism-confirmed loss, not a generic bone-health talking point. Any calcium supplementation must stay under the NIH ODS tolerable upper intake level of 2,500 mg/day for adults and should be discussed with a prescriber, given cardiovascular and renal considerations of calcium supplementation, especially in older adults.

Limits on what this shows

• Key null finding: No significant difference versus disease controls — the deficit may substantially reflect the underlying chronic illness (sun exposure, mobility, diet) rather than the drug itself. This is the meta-analysis's own reported null result and is the reason for the Orange, not Red, grade.
• At-risk subgroups: Patients also being managed for glucocorticoid-induced osteoporosis; limited sun exposure.

Population evidence

Systematic review with meta-analysis of observational studies (JCEM, 2012): serum 25(OH)D in glucocorticoid users averaged 0.5 ng/mL lower than in healthy controls (p=0.03), but showed no significant difference versus disease controls (weighted means 22.4 vs 21.0 ng/mL, p=0.793).

Mechanism

Not established at Tier A/B in sources actually opened for this review; not asserted beyond what the meta-analysis itself supports.

Counter-evidence held on record

Monitor 25(OH)D rather than assume deficiency. The NIH ODS tolerable upper intake level for vitamin D is 50 mcg (2,000 IU)/day for routine supplementation; therapeutic repletion doses used clinically for confirmed deficiency can exceed this under medical supervision, which is outside this dossier's scope.

Limits on what this shows

• Key null finding: Effect described in the label as dose-dependent; not systematically documented at standard low-to-moderate outpatient doses.
• At-risk subgroups: High-dose or IV pulse therapy; concurrent diuretics or beta-agonists.

Regulatory status

DailyMed label, Warnings: "large doses...can cause...increased excretion of potassium"; the label states these effects "are less likely to occur with synthetic derivatives [prednisolone-type] except when used in large doses" — the explicit boundary for this grade.

Population evidence

Label statement plus published case reports of prednisolone-associated hypokalemia and mineralocorticoid-excess presentations (case-level, Tier B for this drug specifically).

Mechanism

Named: mineralocorticoid receptor cross-activity at higher glucocorticoid exposure, promoting renal potassium wasting.

Counter-evidence held on record

Do not self-supplement potassium; NIH ODS has not set a tolerable upper intake level for potassium because excess supplementation carries its own cardiac arrhythmia risk. Serum potassium should be monitored by a prescriber, particularly at higher doses.

Limits on what this shows

• At-risk subgroups: Hypertension, heart failure, renal impairment.

Regulatory status

Same DailyMed label passage as Potassium above: "elevation of blood pressure, salt and water retention," bounded to large doses / less likely with synthetic derivatives except at large doses.

Mechanism

Named: mineralocorticoid receptor activity promoting renal sodium and water retention.

Counter-evidence held on record

This is a retention hazard, not a depletion. Sodium or fluid "supplementation" would be the hazard here, not the remedy. Patients with hypertension, heart failure, or renal impairment need salt-restriction guidance from their prescriber, not sodium repletion advice.

Limits on what this shows

• Key null finding: In a separate rodent study (methylprednisolone, class-level), mitochondrial ATP production and citrate synthase activity were preserved in soleus muscle despite suppressed protein synthesis rates — catabolism and mitochondrial dysfunction are not automatically coupled.
• At-risk subgroups: Prolonged high-dose therapy, malnourished or elderly patients, concurrent immobility.

Population evidence

RCT, 8 healthy men, prednisolone 50 mg/day (25 mg twice daily) for 4 days: functional hepatic nitrogen clearance rose 23% (38.8→47.7 L/h, p<0.05); co-administered growth hormone offset the effect entirely (36.2 L/h, p=0.83 vs control) (human growth hormone / prednisolone nitrogen clearance study).

Mechanism

Named: glucocorticoid-driven amino acid mobilization from muscle protein with increased hepatic ureagenesis, consistent with the general pharmacology reference describing glucocorticoid-stimulated proteolysis and muscle/lymphoid atrophy (Holland-Frei Cancer Medicine).

Distinguish from outcome

This entry is the measured biochemical nitrogen-balance/ureagenesis finding, not the clinical diagnosis of corticosteroid myopathy or muscle wasting, which is an outcome, not a nutrient marker, per this protocol's rules.

Counter-evidence held on record

Adequate dietary protein intake, not a specific "protein supplement" dose, should be discussed with a prescriber or dietitian for patients on prolonged courses. No supplement upper limit applies to dietary protein.

Mechanism

Tier B pharmacology reference (Holland-Frei Cancer Medicine, NCBI Bookshelf): "mineralocorticoids...increase calcium and magnesium excretion, probably due to volume expansion" — stated for the mineralocorticoid/glucocorticoid class generally, not confirmed with prednisolone-specific serum magnesium data.

Population evidence

None found specific to prednisolone despite multiple search phrasings across PubMed, Europe PMC, and general web search.

Counter-evidence held on record

Mechanistic and theoretical only. No dosing recommendation is made for a yellow-tier entry.

Limits on what this shows

• Key null finding: In the rat model, delayed (rather than early) chronic treatment in arthritic animals showed no additional zinc change beyond the underlying inflammation effect.

Population/mechanism evidence

Tier B, prednisolone-specific rat study (adjuvant arthritis model): acute IP 3 mg/kg caused a rapid transient serum zinc decrease with quick recovery; chronic 0.58–0.78 mg/kg/day for 1–4 weeks caused only slight reduction in healthy rats, with additional depletion when treatment began early in arthritic animals (Inflammation Research). Tier C human (methylprednisolone and dexamethasone, IV, normal humans): plasma zinc rose initially then fell below baseline by 12 hours, dose-dependent (ScienceDirect).

Counter-evidence held on record

Mechanistic and time-limited in the animal data available; no human prednisolone-specific deficiency data. No dosing recommendation is made.

Population/mechanism evidence

Tier B, prednisolone-specific rat and mouse study: long-term prednisolone treatment increased circulating bioactive B6 forms (pyridoxal 5'-phosphate and pyridoxal) by inducing hepatic B6-synthesizing enzymes and suppressing catabolic enzymes, without increased urinary excretion (Journal of Pharmacology and Experimental Therapeutics, 2011).

Human confirmation

None found; this is animal evidence only.

Counter-evidence held on record

This directly contradicts the common "prednisone depletes B6" consumer claim in the one animal model studied. It should not be used to justify withholding B6 monitoring in patients with other risk factors, but it also does not support depletion-based B6 supplementation on the strength of this drug's own data.

Population/mechanism evidence

Tier C class extrapolation: cortisone and hydrocortisone (10 mg/kg, not prednisolone) in normal rats caused a moderate decrease in liver ascorbic acid with a rise in dehydroascorbic acid; adrenalectomized rats showed no appreciable change (Metabolism, 1972).

Class extrapolation, explicitly labeled

Cortisone/hydrocortisone are class members with real (if modest) data; prednisolone itself was not studied in this source.

Counter-evidence held on record

Class-level and modest in magnitude even for the drugs that were studied. No dosing recommendation is made.

Limits on what this shows

• Access limitation disclosed: A 1990 human paper titled "Increased Serum Selenium Levels in Patients under Corticosteroid Treatment" (Pharmacology & Toxicology) could not be opened after repeated attempts (Wiley returned HTTP 403 each time); its content is not used to support this grade and is flagged in Sources for a future revision to re-attempt.

Population/mechanism evidence

Tier C class extrapolation: dexamethasone (not prednisolone) in mice, given via drinking water or subcutaneous injection over 1–3 weeks, decreased liver selenium and glutathione peroxidase activity while increasing plasma and brain selenium, interpreted as redistribution rather than net loss, most pronounced at 1 week (British Journal of Nutrition).

Counter-evidence held on record

Where an effect exists in the animal data available, it runs toward redistribution/increase in plasma, not depletion. No depletion-based selenium supplementation is supported by this drug's evidence.