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Tretinoin Bone Health and Density Impact: What the Evidence Actually Shows

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At a glance

  • Drug / topical tretinoin (all-trans retinoic acid)
  • Absorption from a 0.05% cream / under 2% of the dose, after one application and after 28 days of daily use in healthy men [1]
  • Absorption across topical products / 1% to 31%, depending on whether applied to healthy or dermatitic skin [1]
  • Long-term oral etretinate / bone density 85.0% to 90.6% of matched control values at four of five sites [2]
  • High dietary retinol / hip fracture relative risk 1.89, at least 2000 versus under 500 mcg/day [3]

How much tretinoin crosses the skin?

The Renova (tretinoin cream 0.02%) prescribing information states that tretinoin is an endogenous retinoid metabolite of vitamin A that binds intracellular receptors and activates RAR-alpha, RAR-beta and RAR-gamma, and that cutaneous tretinoin levels above physiologic concentrations occur after application of a topical tretinoin product [1].

The label reports that transdermal absorption of tretinoin from various topical formulations ranged from 1% to 31% of the applied dose, depending on whether it was applied to healthy skin or dermatitic skin. It also notes that no percutaneous absorption study was conducted with Renova 0.02% cream in human volunteers [1].

The label's absorption figures for healthy skin come from a 0.05% oil-in-water cream, studied with radiolabeled cream in healthy men. Absorption was under 2% after a single application (seven subjects) and under 2% after 28 days of daily application (seven subjects). Bioavailability was lower after repeated use, and endogenous tretinoin concentrations did not differ significantly between single and repeated dosing [1].

What the bone studies actually measured

None of the studies below tested topical tretinoin.

Oral isotretinoin. Leachman and colleagues measured bone density in young men aged 17 to 25 taking oral isotretinoin 1 mg/kg for cystic acne, and in healthy volunteers aged 19 to 26. Ward triangle density fell a mean 4.4% (P=.03) after six months, and four patients lost more than 9% at that site. The difference in mean change versus controls was significant at the Ward triangle (P=.04) but not at the other sites, and calcium metabolism measures did not change. Density was already lower at all measured sites in the men with cystic acne before treatment [4].

Long-term oral etretinate. Twenty-four patients who had taken at least 50 g of etretinate (15 patients) or isotretinoin (nine patients) for two years or more were compared with age-, sex- and weight-matched control values. Etretinate-group density was 90.6% of control values at the femoral neck, 87.8% at the Ward triangle, 87.8% at the trochanter and 85.0% at the radius. The isotretinoin group did not differ from controls except for higher lumbar spine density [2].

Dietary retinol. Among 72,337 postmenopausal women in the Nurses' Health Study followed from 1980 to 1998, 603 hip fractures from low or moderate trauma occurred. The highest quintile of total vitamin A intake (at least 3000 mcg/day of retinol equivalents) had a relative risk of 1.48 (95% CI 1.05 to 2.07) versus the lowest, and retinol at least 2000 versus under 500 mcg/day gave a relative risk of 1.89 (95% CI 1.33 to 2.68) [3].

What the label warns about

The Renova warnings address the skin: erythema, itching, burning, stinging, peeling and photosensitivity, with instructions to minimize exposure to sunlight and sunlamps and to use sunscreen of at least SPF 15 with protective clothing [1]. In double-blind vehicle-controlled studies of 339 patients applying Renova 0.02% to the face, 32% had skin irritation that was severe, led to temporary discontinuation, or required a mild topical corticosteroid, and about 4% discontinued because of adverse reactions [1].

Frequently asked questions

Does topical tretinoin affect bone density?
Its effect on bone is not established. The bone studies on retinoids involved oral isotretinoin, oral etretinate or high dietary retinol, not topical tretinoin [2][3][4]. The Renova label reports that under 2% of a 0.05% cream was absorbed in healthy men, after one application and after 28 days of daily use [1].
Can retinoids cause bone loss?
Oral isotretinoin at 1 mg/kg for six months was associated with a mean 4.4% drop in density at the Ward triangle in young men, with no significant difference from controls at the other sites [4]. Long-term oral etretinate was linked to density 85.0% to 90.6% of matched control values at four of five sites [2]. Both are oral exposures, not topical tretinoin.
How much tretinoin is absorbed through the skin?
From a 0.05% oil-in-water cream, under 2% of the applied dose was absorbed in healthy men after one application and after 28 days of daily use [1]. Across topical products the label reports 1% to 31%, depending on whether the skin was healthy or dermatitic [1].

References

  1. U.S. National Library of Medicine, DailyMed. Renova tretinoin cream 0.02% (Bausch) prescribing information. Renova tretinoin cream 0.02% (Bausch) label
  2. DiGiovanna JJ, Sollitto RB, Abangan DL, Steinberg SM, Reynolds JC. Osteoporosis is a toxic effect of long-term etretinate therapy. Arch Dermatol. 1995;131(11):1263-7. Osteoporosis is a toxic effect of long-term etretinate therapy
  3. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA. 2002;287(1):47-54. Vitamin A intake and hip fractures among postmenopausal women
  4. Leachman SA, Insogna KL, Katz L, Ellison A, Milstone LM. Bone densities in patients receiving isotretinoin for cystic acne. Arch Dermatol. 1999;135(8):961-5. Bone densities in patients receiving isotretinoin for cystic acne
Evidence overview for tretinoin: Tretinoin Bone Health and Density Impact: What the Evidence Actually Shows