topical steroids and osteoporosis

 Long-term potent topical corticosteroid use may be associated with increased risk of osteoporosis and fractures (see osteoporosis topical steroids jamaderm2021 in dropbox, or doi:10.1001/jamadermatol.2020.4968)

 

Details:

-- 723,251 Danish adults who were treated with potent or very potent topical corticosteroids (TCSs), from 2003-2018

-- mean age 53, 53% women, 20% from each of 5 defined SES groups, few comorbidities (cancer and diabetes 3% each, no comment on others)

-- meds used: psych meds 11%, thiazides 9%, statins 8%, PPIs 7%, contraceptives 7%

-- inhaled steroids 3%, systemic steroids 8%

-- topical steroid doses were translated into equipotent doses of mometasone 1 mg/g

-- all patients had used at least 200 g of mometasone cumulatively, based on filled prescriptions

-- Main outcomes: diagnosis of osteoporosis (as inpatient or outpatient diagnosis) or major osteoporotic fracture (fracture the hip, distal forearm, vertebrae, or humerus)

 

Results:

-- major osteoporotic fracture (MOF), with reference being those using mometasone 200-499 g, which had baseline 81.6 (80.6-82.7) per 10,000 person-years:

    -- 500-999g: nonsignificant 1% increase, HR 1.01 (0.99-1.03), with 88.7 (87.2-90.2) per 10,000 person-years

    -- 1000-1999 g: 5% increase, HR 1.05 (1.02-1.08), with 100.6 (98.4-102.8) per 10,000 person-years

    -- 2000-9999 g: 10% increase, HR 1.10 1.07-1.13), with 113.1 (110.5-115.7) per 10,000 person-years

    -- > 10,000 g: 27% increase, HR 1.27 (1.19-1.35), with 122.3 (115.0-130.1) per 10,000 person-years 

-- osteoporosis), with reference being those using mometasone 200-499 g, which had baseline 36.7 (36.0-37.4) cases per 10,000 person-years:

    -- 500-999g: 43.1 (42.1-44.2) per 10,000 person-years

    -- 1000-1999 g: 50.2 (48.7-51.7) per 10,000 person-years

    -- 2000-9999 g: 55.2 (53.6-57.0) per 10,000 person-years

    -- > 10,000 g: 58.7 (53.8-64.1) per 10,000 person-years

-- similar numbers were found for age-adjusted subgroups analysis for taking osteoporosis medications, and for sustaining vertebral fracture; and for fully adjusted analyses (age, sex, SES, medication use, and comorbidity)

-- assessment for exposure needed to harm, for osteoporosis and MOF:

    -- 500-999g: osteoporosis 4544 person-years; MOF 12,250 person-years

    -- 1000-1999 g: osteoporosis 3029 person-years; MOF 2450 person-years

    -- 2000-9999 g: osteoporosis 2726 person-years; MOF 1225 person-years

    -- > 10,000 g: osteoporosis 1136 person-years; MOF 454 person-years

 

-- doubling of the cumulative TCS dose was associated with a 3% relative risk increase of osteoporosis and MOF, HR 1.03 (1.02-1.04) for both of them

-- overall population attributable risk for osteoporosis was 4.3% (2.7%-5.8%) and for MOF was 2.7% (1.7%-3.8%)

-- the lowest mometasone dose associated with one additional patient to be harmed (454 person-years) was observed for MOF exposure of at least 10,000 g

   

Commentary:

-- this study found an important increase in osteoporosis and MOF in those using potent topical corticosteroids, with a dose-response curve. The resultant increases were calculated to be as many as 4.3% of osteoporosis cases that might have been prevented if not using these potent steroids

    -- inhaled steroids, another topical steroid application, does seem to have a greater risk of osteoporosis or fragility fracture with higher cumulative doses

    -- a likely relevant issue: inhaled steroids or steroid joint injections can be associated with Cushings syndrome if the patient is on ritonavir or cobicistat (both inhibit metabolism of the steroids): see http://gmodestmedblogs.blogspot.com/2019/05/hiv-meds-local-steroids-and-cushings.html . seems like would be relevant to TCS, since they do seem to have systemic absorption....

        -- and, prior studies have found systemic effects of very high dose of TCSs, including striae, adrenal suppression, Cushing’s syndrome, and Addison’s crisis after quick withdrawal

        -- recent studies of also found an increased risk of type II diabetes in individuals on TCSs

-- in Denmark, high potency TCSs are used frequently and in high quantities for such conditions as atopic dermatitis (3% of Danish adults) and psoriasis (8% of adults)

-- though the exposure level needed to harm patients (ENH) seems low, and an individual patient is unlikely to be harmed, as a point of reference: >40 mg per day of oral prednisolone for up to 30 days has an ENH of 115 person-years, whereas that for high-level users of TCSs is 454 person-years. so, the effect of the transdermal steroids is much smaller than even a relatively small amount of oral steroids, but is still having some untoward adverse systemic effects on bone

    -- and, glucocorticoid-induced osteoporosis is the most common secondary cause of osteoporosis

-- chronic inflammatory diseases, such as rheumatoid arthritis and psoriasis, may be associated with increased risk of osteoporosis. In this study they assessed both patients with and without severe psoriasis, and further analysis eliminating those with severe psoriasis found virtually identical results

-- these types of studies display the trove of information that can be generated by health systems where the whole population is included (because of universal healthcare, a single system of care, and linkable databases including clinical problems with patient-level information, and, in this case, prescriptions filled)

 

Limitations:

-- in this study they did not have data on other risk factors for osteoporosis, such as smoking or being underweight, or vitamin D status

-- there were no data on what anatomic sites received the TCSs; there is as much is a 42-fold difference in skin penetration in different anatomical regions; and there is also differential absorption depending on skin integrity

-- the vehicle for the TCS was not known, and ointments for example may lead to prolonged bioavailability and potential systemic effects

-- the study is based on prescriptions filled and not specifics of how much was applied or absorbed

-- there were minimal data presented disaggregating the relationship between the indication for TCSs, the quantity of TCSs prescribed, and osteoporosis/MOF outcomes

-- it would have been useful to quantify the underlying inflammatory state, perhaps by a few different markers

 

So, a few points from this article:

-- high potency TCSs are prescribed quite frequently, often without much concern for the quantity applied per skin surface area

-- those people requiring sustained long-term high dose TCSs should also have appropriate additional therapies to minimize this dosage, including alternative non-steroid therapies (for example, in those with atopic dermatitis/eczema, using emollients; minimizing triggers that are exacerbating factors such as irritant soaps, common skin infections, allergens)

-- as per most medications, we clinicians should prescribe the lowest effective quantity and dose, including TCSs. Many skin conditions do require high potency TCS initially to work, though many times patients can be transitioned to lower potency ones after the skin condition has improved or just nonsteroid therapies

--and, patients should know the potential risks for high potency steroids (and we clinicians should not simply refill a high potency steroid when the patient or pharmacy requests it, but should make sure that is what is needed for continued care)

geoff

 

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