osteoporosis

Interview with Esa M. Davis, MD, MPH, USPSTF member and coauthor of Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement. Hosted by JAMA Editor in Chief Kirsten Bibbins-Domingo, PhD, MD, MAS.

Osteoporotic fractures, especially hip fractures, are associated with mobility limitations, chronic disability, loss of independence, and reduced quality of life.

Several randomized trials have demonstrated the benefit of drug treatment in reducing clinical fractures among postmenopausal women with existing vertebral fractures or bone mineral density (BMD) T-scores of −2.5 or lower and among adults aged 50 years and older with recent hip fracture.

Thus, osteoporosis in the clinical setting should be diagnosed in patients with a history of hip or clinical vertebral fracture not due to excessive trauma, those with existing radiographic vertebral fractures, and those with a BMD T-score of −2.5 or lower at the hip (femoral neck or total hip) or lumbar spine. In the absence of a history of hip or vertebral fracture, osteoporosis screening is aimed at identifying individuals with a BMD T-score of −2.5 or lower because those individuals may be candidates for osteoporosis pharmacotherapy. The BMD T-score quantifies the difference (expressed in standard deviations) between a patient’s BMD and the average BMD of young adult white women (reference group).

BACKGROUND:

Optimal long-term osteoporosis drug treatment (ODT) is uncertain.

PURPOSE:

To summarize the effects of long-term ODT and ODT discontinuation and holidays.

DATA SOURCES:

Electronic bibliographic databases (January 1995 to October 2018) and systematic review bibliographies.

STUDY SELECTION:

48 studies that enrolled men or postmenopausal women aged 50 years or older who were being investigated or treated for fracture prevention, compared long-term ODT (>3 years) versus control or ODT continuation versus discontinuation, reported incident fractures (for trials) or harms (for trials and observational studies), and had low or medium risk of bias (ROB).

DATA EXTRACTION:

Two reviewers independently rated ROB and strength of evidence (SOE). One extracted data; another verified accuracy.

DATA SYNTHESIS:

Thirty-five trials (9 unique studies) and 13 observational studies (11 unique studies) had low or medium ROB. In women with osteoporosis, 4 years of alendronate reduced clinical fractures (hazard ratio [HR], 0.64 [95% CI, 0.50 to 0.82]) and radiographic vertebral fractures (both moderate SOE), whereas 4 years of raloxifene reduced vertebral but not nonvertebral fractures. In women with osteopenia or osteoporosis, 6 years of zoledronic acid reduced clinical fractures (HR, 0.73 [CI, 0.60 to 0.90]), including nonvertebral fractures (high SOE) and clinical vertebral fractures (moderate SOE). Long-term bisphosphonates increased risk for 2 rare harms: atypical femoral fractures (low SOE) and osteonecrosis of the jaw (mostly low SOE). In women with unspecified osteoporosis status, 5 to 7 years of hormone therapyreduced clinical fractures (high SOE), including hip fractures (moderate SOE), but increased serious harms. After 3 to 5 years of treatment, bisphosphonate continuation versus discontinuation reduced radiographic vertebral fractures (zoledronic acid; low SOE) and clinical vertebral fractures (alendronate; moderate SOE) but not nonvertebral fractures (low SOE).

LIMITATION:

No trials studied men, clinical fracture data were sparse, methods for estimating harms were heterogeneous, and no trials compared sequential treatments or different durations of drug holidays.

CONCLUSION:

Long-term alendronate and zoledronic acid therapies reduce fracture risk in women with osteoporosis. Long-termbisphosphonate treatment may increase risk for rare adverse events, and continuing treatment beyond 3 to 5 years may reduce risk for vertebral fractures. Long-term hormone therapy reduces hip fracture risks but has serious harms.

PRIMARY FUNDING SOURCE:

National Institutes of Health and Agency for Healthcare Research and Quality. (PROSPERO: CRD42018087006).

Objective. To summarize the effects of long-term osteoporosis drug treatment (ODT) and ODT discontinuation and holidays on fractures and harms.

Data sources. MEDLINE®, Embase®, and Cochrane databases from 1995 to October 2018; ClinicalTrials.gov; bibliographies of relevant systematic reviews.

Review methods. We defined long-term ODT as >3 years and ODT holidays as discontinuation for ≥1 year after ≥1 year of use. Trials were used for incident fractures and harms, and controlled observational studies were included for additional harms. Two investigators rated risk of bias. For studies with low or medium risk of bias, one investigator extracted data and a second verified accuracy. Two investigators graded strength of evidence (SOE).

Results. Sixty-one English-language studies were included. In women with osteoporosis, 4 years of alendronate reduced clinical fractures (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.50, 0.82]) (moderate SOE) and radiographic vertebral fractures (HR 0.50 [95% CI 0.31, 0.82]) (moderate SOE), while 4 years of raloxifene reduced clinical vertebral fractures (relative risk 0.58 [95% CI 0.43, 0.79]) (high SOE), but not hip (moderate SOE) or nonvertebral fractures (high SOE). In women with osteopenia or osteoporosis, 6 years of zoledronate reduced incident clinical fractures (HR 0.73 [95% CI 0.60, 0.90]) (moderate SOE) and clinical vertebral fractures (HR 0.41 [95% CI 0.22, 0.75]) (moderate SOE). In postmenopausal women with unknown osteoporosis or osteopenia status, both long-term oral estrogen and estrogen/progestin reduced clinical fractures (high SOE) and hip fractures (moderate SOE). After 3–5 years of prior treatment, continuation of zoledronate or alendronate versus drug holiday inconsistently reduced incident vertebral fracture outcomes (radiographic only for zoledronate [low SOE], clinical only for alendronate [moderate SOE]), but did not reduce nonvertebral fractures (low SOE). Hormone therapies increased cardiovascular events, mild cognitive impairment or dementia, and other harms. Observational studies showed that long-term bisphosphonates may increase atypical femoral fractures (AFF) (low SOE) and osteonecrosis of the jaw (low SOE in 2 comparisons, insufficient in 1).

Limitations. Most data were from white, healthy, postmenopausal women, limiting generalizability. Trials often had low power for incident clinical fractures. No trials compared active treatments, sequential treatments, or different durations of drug holidays. Harms and controls were inconsistently defined.

Conclusions. Long-term alendronate, zoledronate, and oral hormone therapy reduced nonvertebral fractures in older women, with oral hormone therapy also reducing hip fractures. While absolute reductions in typical fractures with long-term bisphosphonates are large relative to increases in AFF, reduced hip fracture risk with oral hormone therapy appears offset by increased risk of serious harms. Evidence is limited regarding ODT holidays for fractures and harms. Future research is needed, including randomized trials comparing ODT holiday durations and sequential treatments powered for clinical fractures, and controlled cohort studies of ODT holidays to estimate rare harms.