osteoporosis: time until bisphosphonate benefit

 A recent meta-analysis assessed the time to show benefit of bisphosphonate therapy in preventing fractures in postmenopausal women with osteoporosis, which is helpful in determining for which women these meds are not indicated (see osteoporosis bisphosph time to benefit jamaintmed2021 I n dropbox, or doi:10.1001/jamainternmed.2021.6745 )

Details:

--10 high quality RCTs were identified that involved postmenopausal women with osteoporosis based on existing vertebral fractures or bone mineral density (BMD) of -2.5 or lower; the studies each ranged from 994 to 7765 women involved

--23,384 women identified and followed

--age range 63-74, follow-up duration 12-48 months

--doses of meds: alendronate 5-20 mg/d, risedronate 2.5-5 mg/d, zoledronic acid 5 mg/d

--main outcomes: time to 3 different absolute risk reductions (ARRs) with differing thresholds (0.002, 0.005, and 0.010) for the first nonvertebral fracture (these ARRs reflects 1 event per 500, 1 per 200 and 1 per 100 women on meds)

--secondary outcomes: 4 ARRs (0.001, 0.002, 0.005, and 0.010) for hip fracture, any clinical fracture, and clinical vertebral fractures

Results:

--ARR 0.010: 12.4 months (6.3-18.4 months) to avoid 1 nonvertebral fracture per 100 postmenopausal women on bisphosphonates

--ARR 0.005: 6.5 months (2.2-10.9 months) to avoid 1 nonvertebral facture per 200 menopausal women

--ARR 0.002: 3.3 months (0.2-6.5 months) to avoid 1 nonvertebral facture per 500 menopausal women

    -- ie, fracture risk is close to linear per ARR

-- here is graph of risk over time for ARR 0.010

 

--for clinical vertebral fractures:

    -- ARR of 0.005: 200 women would need medication for 12.1 months ( 6.6-17.8 months) to avoid 1 clinical vertebral fracture

--for hip fracture:

    -- ARR of 0.005: 200 women would need med for 20.3 months ( 11.0-29.7 months) to avoid 1 hip fracture

-- for any clinical fracture:

    -- ARR of 0.005: 200 women would need med for 7.7 months ( 3.3-12.1 months) to avoid 1 clinical fracture

Commentary:

--osteoporotic fractures are common (1.9 million in the US per year), expensive ($57B cost), and are associated with significant morbidity (functional impairment, reduced quality of life) and increased mortality

    --as a side note, osteoporosis is often not identified (25% of women get a BMD, despite recommendations). And, even when identified, may not be treated aggressively enough: decreasing numbers of people with a history of a hip fracture get meds, and they are at high risk for another one, see: http://gmodestmedblogs.blogspot.com/2018/07/decreasing-use-of-osteoporosis-meds.html )

    -- there is also utility of the FRAX score, which takes into account important other factors, besides BMD, that increase fracture risk: https://www.sheffield.ac.uk/FRAX/ 

--the finding that bisphosphonates seem to require 12.4 months to prevent 1 nonvertebral fracture per 100 women with osteoporosis is clinically very relevant. these fractures (esp hip fractures) are associated with lots of morbidity and mortality. and these fractures increase markedly in frequency with age. so, in those with anticipated shorter life expectancies than 1 year or so, not prescribing meds will likely decrease the very real risk of harms from meds (esophageal inflammation/bleeding, and the much less common but pretty debilitating jaw osteonecrosis/atypical hip fractures), as well as the polypharmacy, including a difficult pill to take: once a week, sitting or standing, with a full glass of water, and wait 30 minutes prior to food/other meds

    --the website e-prognosis is useful in estimating life expectancy (see https://eprognosis.ucsf.edu/calculators/ ), where an 86yo with BMI<25, fair-to-poor health, heart failure, diabetes, former smoker, unable to walk 1/4 mile, and needs help at home with ADLs, has a life expectancy of 2.9 years. and less if more comorbidities or more advanced age. so, helpful to guide us in making decision as to when to offer meds

Limitations

--this study posits different scenarios of risk: from 1 in 100 to 1 in 1000 postmenopausal women having a fracture. the actual number needed to be treated varies depending on the full risk scenario (including other risk factors, eg as in the FRAX score), and this would likely vary based on discussions between the clinician and patient in terms of the patient's values and fears

--they define osteoporosis including BMD less than -2.5.  but the risk of fracture is related to the degree of osteoporosis. so the actual age when benefits outweigh risks may be quite different for a woman with BMD of -4.5. Which means that these results may not be generalizable to all women with osteoporosis

--the focus here was on nonvertebral fractures, with a secondary focus on clinical vertebral fractures. About 30% of vertebral fractures are symptomatic and about 75% of those with symptomatic fractures have chronic pain. but even with an asymptomatic vertebral fracture (happens 70% of the time), these women are predisposed to more vertebral and other fractures (and, any vertebral fracture is an indication of osteoporosis and a strong consideration of meds, again with the proviso regarding the time to getting benefit from meds)

--it would be useful to know these numbers for men, where the lifetime risk of a hip fracture is 6% vs 17.5% in women, but still a significant cause of morbidity and mortality

so, a useful talking point and decision point in treating postmenopausal women, which reinforces a few things:

--the importance of assessing postmenopausal women for osteoporosis in the first place (not done enough, as noted above)

--the importance of reinforcing nonpharmacologic therapies in all postmenopausal women: adequate vitamin D and calcium, regular exercise, stopping alcohol/smoking, and helping decrease fall risk

--the efficacy of meds, which do work quickly to reduce fracture risk, when the anticipated life expectancy is appropriate for the patient

--the utility of starting meds at as early an age as indicated, since bisphosphonates do not increase bone mass much (though likely help with bony microstructure of the bones: see https://pubmed.ncbi.nlm.nih.gov/26879146/), so best to prevent bone loss as much as possible by identifying higher risk women and treating them as needed

--and the importance of shared decision-making in women at high risk for a fracture....

geoff

 

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