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Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement

Author/s: 
US Preventive Services Task Force

Importance Osteoporotic fractures are associated with psychological distress, subsequent fractures, loss of independence, reduced ability to perform activities of daily living, and death.

Objective The US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the evidence on the benefits and harms of screening for osteoporosis to prevent fractures in adults 40 years or older with no known diagnosis of osteoporosis or history of fragility fracture.

Population Adults 40 years or older without known osteoporosis or history of fragility fractures.

Evidence Assessment The USPSTF concludes with moderate certainty that screening for osteoporosis to prevent osteoporotic fractures in women 65 years or older has moderate net benefit. The USPSTF concludes with moderate certainty that screening for osteoporosis to prevent osteoporotic fractures in postmenopausal women younger than 65 years at increased risk has moderate net benefit. The USPSTF concludes that the evidence is insufficient and the balance of benefits and harms for screening for osteoporosis to prevent osteoporotic fractures in men cannot be determined.

Recommendation The USPSTF recommends screening for osteoporosis to prevent osteoporotic fractures in women 65 years or older. (B recommendation) The USPSTF recommends screening for osteoporosis to prevent osteoporotic fractures in postmenopausal women younger than 65 years who are at increased risk for an osteoporotic fracture as estimated by clinical risk assessment. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis to prevent osteoporotic fractures in men. (I statement)

Keywords 
women osteoporosis female

Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement

Author/s: 
US Preventive Services Task Force, Wanda K Nicholson, Michael Silverstein, John B Wong

Importance: Osteoporotic fractures are associated with psychological distress, subsequent fractures, loss of independence, reduced ability to perform activities of daily living, and death.

Objective: The US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the evidence on the benefits and harms of screening for osteoporosis to prevent fractures in adults 40 years or older with no known diagnosis of osteoporosis or history of fragility fracture.

Population: Adults 40 years or older without known osteoporosis or history of fragility fractures.

Evidence assessment: The USPSTF concludes with moderate certainty that screening for osteoporosis to prevent osteoporotic fractures in women 65 years or older has moderate net benefit. The USPSTF concludes with moderate certainty that screening for osteoporosis to prevent osteoporotic fractures in postmenopausal women younger than 65 years at increased risk has moderate net benefit. The USPSTF concludes that the evidence is insufficient and the balance of benefits and harms for screening for osteoporosis to prevent osteoporotic fractures in men cannot be determined.

Recommendation: The USPSTF recommends screening for osteoporosis to prevent osteoporotic fractures in women 65 years or older. (B recommendation) The USPSTF recommends screening for osteoporosis to prevent osteoporotic fractures in postmenopausal women younger than 65 years who are at increased risk for an osteoporotic fracture as estimated by clinical risk assessment. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis to prevent osteoporotic fractures in men. (I statement).

Keywords 
osteoporosis Osteoporotic Fractures

Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women

Author/s: 
Wells, G. A., Hsieh, S., Zheng, C., Peterson, J., Tugwell, P., Liu, W.

Background: Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Risedronate belongs to the bisphosphonate class of drugs which act to inhibit bone resorption by interfering with the activity of osteoclasts. This is an update of a Cochrane Review that was originally published in 2003.

Objectives: We assessed the benefits and harms of risedronate in the primary and secondary prevention of osteoporotic fractures for postmenopausal women at lower and higher risk for fractures, respectively.

Search methods: With broader and updated strategies, we searched the Cochrane Central Register of Control Trials (CENTRAL), MEDLINE and Embase. A grey literature search, including the online databases ClinicalTrials.gov, International Clinical Trials Registry Platform (ICTRP), and drug approval agencies, as well as bibliography checks of relevant systematic reviews was also performed. Eligible trials published between 1966 to 24 March 2021 were identified.

Selection criteria: We included randomised controlled trials that assessed the benefits and harms of risedronate in the prevention of fractures for postmenopausal women. Participants must have received at least one year of risedronate, placebo or other anti-osteoporotic drugs, with or without concurrent calcium/vitamin D. Major outcomes were clinical vertebral, non-vertebral, hip and wrist fractures, withdrawals due to adverse events, and serious adverse events. In the interest of clinical relevance and applicability, we classified a study as secondary prevention if its population fulfilled more than one of the following hierarchical criteria: a diagnosis of osteoporosis, a history of vertebral fractures, low bone mineral density (BMD)T score ≤ -2.5, and age ≥ 75 years old. If none of these criteria was met, the study was considered to be primary prevention.

Data collection and analysis: We used standard methodology expected by Cochrane. We pooled the relative risk (RR) of fractures using a fixed-effect model based on the expectation that the clinical and methodological characteristics of the respective primary and secondary prevention studies would be homogeneous, and the experience from the previous review suggesting that there would be a small number of studies. The base case included the data available for the longest treatment period in each placebo-controlled trial and a >15% relative change was considered clinically important. The main findings of the review were presented in summary of findings tables, using the GRADE approach. In addition, we looked at benefit and harm comparisons between different dosage regimens for risedronate and between risedronate and other anti-osteoporotic drugs.

Main results: Forty-three trials fulfilled the eligibility criteria, among which 33 studies (27,348 participants) reported data that could be extracted and quantitatively synthesized. We had concerns about particular domains of risk of bias in each trial. Selection bias was the most frequent concern, with only 24% of the studies describing appropriate methods for both sequence generation and allocation concealment. Fifty per cent and 39% of the studies reporting benefit and harm outcomes, respectively, were subject to high risk. None of the studies included in the quantitative syntheses were judged to be at low risk of bias in all seven domains. The results described below pertain to the comparisons for daily risedronate 5 mg versus placebo which reported major outcomes. Other comparisons are described in the full text. For primary prevention, low- to very low-certainty evidence was collected from four studies (one to two years in length) including 989 postmenopausal women at lower risk of fractures. Risedronate 5 mg/day may make little or no difference to wrist fractures [RR 0.48 ( 95% CI 0.03 to 7.50; two studies, 243 participants); absolute risk reduction (ARR) 0.6% fewer (95% CI 1% fewer to 7% more)] and withdrawals due to adverse events [RR 0.67 (95% CI 0.38 to 1.18; three studies, 748 participants); ARR 2% fewer (95% CI 5% fewer to 1% more)], based on low-certainty evidence. However, its preventive effects on non-vertebral fractures and serious adverse events are not known due to the very low-certainty evidence. There were zero clinical vertebral and hip fractures reported therefore the effects of risedronate for these outcomes are not estimable. For secondary prevention, nine studies (one to three years in length) including 14,354 postmenopausal women at higher risk of fractures provided evidence. Risedronate 5 mg/day probably prevents non-vertebral fractures [RR 0.80 (95% CI 0.72 to 0.90; six studies, 12,173 participants); RRR 20% (95% CI 10% to 28%) and ARR 2% fewer (95% CI 1% fewer to 3% fewer), moderate certainty], and may reduce hip fractures [RR 0.73 (95% CI 0.56 to 0.94); RRR 27% (95% CI 6% to 44%) and ARR 1% fewer (95% CI 0.2% fewer to 1% fewer), low certainty]. Both of these effects are probably clinically important. However, risedronate's effects are not known for wrist fractures [RR 0.64 (95% CI 0.33 to 1.24); three studies,1746 participants); ARR 1% fewer (95% CI 2% fewer to 1% more), very-low certainty] and not estimable for clinical vertebral fractures due to zero events reported (low certainty). Risedronate results in little to no difference in withdrawals due to adverse events [RR 0.98 (95% CI 0.90 to 1.07; eight studies, 9529 participants); ARR 0.3% fewer (95% CI 2% fewer to 1% more); 16.9% in risedronate versus 17.2% in control, high certainty] and probably results in little to no difference in serious adverse events [RR 1.00 (95% CI 0.94 to 1.07; six studies, 9435 participants); ARR 0% fewer (95% CI 2% fewer to 2% more; 29.2% in both groups, moderate certainty).

Authors' conclusions: This update recaps the key findings from our previous review that, for secondary prevention, risedronate 5 mg/day probably prevents non-vertebral fracture, and may reduce the risk of hip fractures. We are uncertain on whether risedronate 5mg/day reduces clinical vertebral and wrist fractures. Compared to placebo, risedronate probably does not increase the risk of serious adverse events. For primary prevention, the benefit and harms of risedronate were supported by limited evidence with high uncertainty.

Keywords 
Risedronate prevention Postmenopausal Women osteoporosis

Osteoporosis Screening in Younger Postmenopausal Women

Author/s: 
Crandall, C.J., Ensrud, Kristine E.

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).

Keywords 
osteoporosis screening

Diagnosis of osteoporosis in statin-treated patients is dose-dependent

Author/s: 
Leutner, M., Matzhold, C., Bellach, L., Deischinger, C., Harreiter, J., Thurner, S., Klimek, P., Kautzky-Willer, A.

OBJECTIVE:

Whether HMG-CoA-reductase inhibition, the main mechanism of statins, plays a role in the pathogenesis of osteoporosis, is not entirely known so far. Consequently, this study was set out to investigate the relationship of different kinds and dosages of statins with osteoporosis, hypothesising that the inhibition of the synthesis of cholesterol could influence sex-hormones and therefore the diagnosis of osteoporosis.

METHODS:

Medical claims data of all Austrians from 2006 to 2007 was used to identify all patients treated with statins to compute their daily defined dose averages of six different types of statins. We applied multiple logistic regression to analyse the dose-dependent risks of being diagnosed with osteoporosis for each statin individually.

RESULTS:

In the general study population, statin treatment was associated with an overrepresentation of diagnosed osteoporosis compared with controls (OR: 3.62, 95% CI 3.55 to 3.69, p<0.01). There was a highly non-trivial dependence of statin dosage with the ORs of osteoporosis. Osteoporosis was underrepresented in low-dose statin treatment (0-10 mg per day), including lovastatin (OR: 0.39, CI 0.18 to 0.84, p<0.05), pravastatin (OR: 0.68, 95% CI 0.52 to 0.89, p<0.01), simvastatin (OR: 0.70, 95% CI 0.56 to 0.86, p<0.01) and rosuvastatin (OR: 0.69, 95% CI 0.55 to 0.87, p<0.01). However, the exceeding of the 40 mg threshold for simvastatin (OR: 1.64, 95% CI 1.31 to 2.07, p<0.01), and the exceeding of a 20 mg threshold for atorvastatin (OR: 1.78, 95% CI 1.41 to 2.23, p<0.01) and for rosuvastatin (OR: 2.04, 95% CI 1.31 to 3.18, p<0.01) was related to an overrepresentation of osteoporosis.

CONCLUSION:

Our results show that the diagnosis of osteoporosis in statin-treated patients is dose-dependent. Thus, osteoporosis is underrepresented in low-dose and overrepresented in high-dose statin treatment, demonstrating the importance of future studies' taking dose-dependency into account when investigating the relationship between statins and osteoporosis.

Keywords 
dose-dependency osteoporosis statin

Long-Term Drug Therapy and Drug Holidays for Osteoporosis Fracture Prevention: A Systematic Review

Author/s: 
Fink, Howard A., MacDonald, Roderick, Forte, Mary L., Rosebush, Christina E., Ensrud, Kristine E., Schousboe, John T., Nelson, Victoria A., Ullman, Kristen, Butler, M., Olson, Carin M., Taylor, Brent C., Brasure, Michelle, Wilt, Timothy J.

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).

Keywords 
bias hip fracture postmenopause alendronate fracture osteoporosis Research

Hip Fractures in Older Adults in 2019

Author/s: 
Berry, Sarah D., Kiel, Douglas P., Colón-Emeric, Cathleen

The incidence of osteoporotic fracture increases exponentially throughout life, as does the risk of the devastating consequences of these fractures, including functional decline, institutionalization, mortality, and destitution.1 Adults in their eighth and ninth decades of life are less likely to be screened and treated for osteoporosis than younger individuals. Guidelines for pharmacologic treatment suggest using 10-year fracture risk estimations, but they do not address decision making for patients with life expectancies less than 10 years. Further, existing fracture risk calculators do not include many comorbidities or frailty characteristics common in older adults that influence risk-benefit assessment when considering pharmacologic treatment as a preventive measure for osteoporosis.

An approach to fracture prevention in older community-dwelling adults is reviewed, including an estimation of fracture risk and life expectancy, shared decision making for pharmacologic interventions, and important nonpharmacologic prevention strategies.

Keywords 
hip fractures osteoporosis

Long-Term Drug Therapy and Drug Holidays for Osteoporosis Fracture Prevention: A Systematic Review

Author/s: 
Fink, Howard A., MacDonald, Roderick, Forte, Mary L., Rosebush, Christina E., Ensrud, Kristine E., Schousboe, John T., Nelson, Victoria A., Ullman, Kristen, Butler, Mary, Olson, Carin M., Taylor, Brent C., Brasure, Michelle, Wilt, Timothy J.

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.

Keywords 
post-menopausal osteoporosis osteoporosis
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