National Institutes of Health Pathways to Prevention Workshop: Research Gaps for Long-Term Drug Therapies for Osteoporotic Fracture Prevention

Albert Siu; Heather Allore; Darryl Brown; Susan T. Charles; Matthew Lohman

doi:10.7326/M19-0961

Abstract

On 30 and 31 October 2018, the National Institutes of Health convened the Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention to assess the available evidence on long-term (>3 years) use of drug therapies to prevent osteoporotic fractures and identify research gaps and needs for advancing the field. The workshop was cosponsored by the NIH Office of Disease Prevention (ODP), National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute on Aging. A multidisciplinary working group developed the agenda, and an Evidence-based Practice Center prepared an evidence report through a contract with the Agency for Healthcare Research and Quality to facilitate the discussion. During the 1.5-day workshop, invited experts discussed the body of evidence and attendees had the opportunity to comment during open discussions. After data from the evidence report, expert presentations, and public comments were weighed, an unbiased independent panel prepared a draft report that was posted on the ODP Web site for 5 weeks for public comment. This final report summarizes the panel's findings and recommendations. Current gaps in knowledge are highlighted, and a set of recommendations for new, strengthened research to better inform the long-term use of osteoporotic drug therapies is delineated.

Advances in understanding the biology of osteoporosis have resulted in several medications that have been demonstrated to reduce fracture risk (1, 2). However, access to screening, medication costs, and patient concerns about rare adverse effects of antiresorptive treatments have coincided with decreased prescribing of osteoporosis drug therapy (ODT) and a leveling off in the incidence of osteoporotic hip fractures (3–5).

Osteoporosis is a skeletal disorder that compromises bone strength (6) and increases the likelihood of fractures. Loss of bone mass is associated with aging; hence, osteoporosis primarily affects older people (7). Among U.S. adults older than 50 years, it is estimated that 8 million women and 2 million men have osteoporosis (8), and 27 million women and 16 million men have low bone mass (8). It is projected that by 2025, five fractures will occur for every 100 people older than 65 years, and total U.S. health care costs attributable to fractures will reach $25 billion annually (7).

Nonpharmacologic approaches to manage osteoporosis, including adequate calcium and vitamin D intake and physical activity, can positively affect bone mass. Coupled with preventing falls and limiting modifiable risk factors, such as smoking and alcohol use, these measures can help reduce a person's risk for osteoporotic fractures (9). Furthermore, pharmacologic treatments may be prescribed to prevent fractures for people who have very low bone mineral density (BMD) or a prior fragility fracture, and the U.S. Food and Drug Administration has approved antiresorptive treatments that inhibit bone resorption and anabolic treatments that stimulate bone formation. Nevertheless, many people at high fracture risk remain untreated. Less than 20% of women received osteoporosis treatment in the year after diagnosis of an initial fragility fracture, and compliance rates are low (7).

On 30 and 31 October 2018, the National Institutes of Health (NIH) convened the Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention to assess the available scientific evidence to better understand the clinical benefits and harms of ODTs, with the aim of identifying research opportunities to fill gaps in our understanding of long-term treatment of osteoporosis. The workshop, cosponsored by the NIH Office of Disease Prevention (ODP), the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the National Institute on Aging, brought together osteoporosis experts and advocates. The ODP commissioned a systematic evidence review on long-term (>3 years) ODT use and fractures, and other researchers were invited to present evidence. Intermediate outcomes, such as BMD, and the more established side effects and adverse outcomes were discussed but were not the major focus. This report focuses on research gaps for long-term (>3 years) ODT use. To complement the commissioned review, this report relied on other systematic reviews and studies presented by speakers.

Evidence Regarding Benefits and Harms of Long-Term ODTs

Although varied in treatment regimens and outcomes assessment, trials have shown the safe and effective use of ODTs with 3 to 5 years of exposure in reducing the incidence of vertebral fractures in postmenopausal white women (1). Shorter-term ODT exposure was reviewed previously in the context of an earlier systematic review (2). Studies (2, 10–12) have shown that some ODTs reduce the incidence of nonvertebral, including hip, fractures. The workshop participants noted the importance of fracture on patient morbidity and survival; however, the trial results presented no data on nonfracture patient outcomes or sequelae of fractures, such as functional status, mobility, hospitalizations, and nursing home placement. There was limited or no evidence on whether patient characteristics would result in different fracture outcomes with these treatments (referred to as “effect modification” hereafter), because individual studies were underpowered to detect changes in outcomes or not large enough to maintain adequate type I error rates for multiple comparisons.

Many of the side effects and possible adverse outcomes associated with ODT are documented elsewhere. The workshop presented rare and serious complications thought to be specific to selected antiresorptive therapies: atypical femoral fractures (AFFs) and osteonecrosis of the jaw (ONJ). These complications have been the subject of advisories from regulators and professional societies. Evidence of the incidence of these complications is limited owing to their rarity and lack of studies designed to systematically identify and ascertain these adverse events. These events have been variably defined; some studies report (13) on subtrochanteric and femoral shaft fractures that may not have had all the radiographic characteristics of AFFs.

Evidence from trials is nonexistent or limited on AFF and ONJ for antiresorptive ODTs (14, 15), and these adverse effects have not been associated with anabolic ODTs. The best available data, despite their limitations, come from observational studies and postmarketing surveillance. This work suggests that the age-adjusted incidence rates for AFFs were 1.78 per 100 000 person-years (95% CI, 1.5 to 2.0 per 100 000 person-years) with bisphosphonate exposure of 0.1 to 1.9 years, and increased to 113.1 per 100 000 person-years (CI, 69.3 to 156.8 per 100 000 persons per year) with bisphosphonate exposure of 8 to 9.9 years (16). For ONJ, the incidence is 1 to 69 per 100 000 patient-years with oral bisphosphonates and 0 to 90 per 100 000 patient-years with intravenous bisphosphonates. These incidence rates are marginally higher than those of the general patient population (1, 2, 13, 17).

The harms of estrogen treatment and estrogen plus progestin treatment should be considered (strokes, invasive breast cancer, pulmonary embolism, and dementia) because they exceed benefits in most postmenopausal women. Effect modification suggested short-term use of estrogen to reduce the risk for fractures remains in consideration for those with postmenopausal symptoms or younger women who have had a hysterectomy. The American College of Obstetricians and Gynecologists and the American College of Physicians have listed several contraindications to the use of estrogens for osteoporosis (11, 18).

Several trials have examined the safety and effectiveness of anabolic agents. However, they were considered out of scope for the systematic review because they are limited to a 2-year lifetime exposure and have a boxed warning based on animal toxicology studies showing an increased risk for osteosarcoma with long-term, high-dose administration.

Current Gaps in Knowledge

Notably, in the case of both benefits and harms, trials provide evidence mainly for white postmenopausal women, whereas other populations (for example, men, spectrum of race and ethnicities, residents in facilities, and people with advanced and multiple comorbid conditions) were absent or underrepresented. Evidence for ODTs is lacking for people who meet neither BMD nor fracture criteria for osteoporosis but are at high risk owing to other health, genetic, or medication use factors. Given that most trial participants did not represent the true potential patient population, estimates on benefits and harms may differ in actual practice.

Few trials extended beyond 5 years, but several observational studies provided limited evidence on potential benefits and harms from longer-term use (1, 10). Evidence is lacking for non–fracture patient outcomes and fracture sequelae that patients may prioritize when making treatment decisions. Gaps exist in how to use information on bone biomarkers and other patient characteristics, such as concurrent medication use, that may modify the effects of ODT on the risk for fractures and their sequelae.

Inability to rigorously estimate effect modification for subpopulations was in part because of limitations in trials designed primarily for regulatory approval. Although there have been many participants in ODT trials, analyses that pool patient-level data are limited to initial work on bone turnover markers and BMD. This approach could be potentially useful for addressing some of the gaps in knowledge of effect modification by increasing power to detect differences in outcomes by a given marker or BMD value.

Drug Holidays

Uncertainty regarding the long-term effects of ODTs has heightened interest in periods of medication discontinuation, or “drug holidays,” as a means of minimizing potential harms. Drug holidays for bisphosphonates are of primary interest, because evidence suggests that accumulation of bisphosphonates in bone may impede normal remodeling and repair and potentially predispose to ONJ and AFF. Similar concerns exist regarding risk for ONJ and AFF with denosumab therapy.

Bisphosphonate Drug Holidays

Evidence gaps limit evaluation of potential harms and benefits of drug holidays for antiresorptive medications. The evidence comes from a limited number of efficacy trials and their extensions, and findings are mixed with regard to risk for incident fractures associated with placebo versus continued bisphosphonate use. Discontinuation of alendronate for 5 years was associated with greater risk for incident vertebral fracture but not nonvertebral or hip fracture (19). Similarly, discontinuation of zoledronate was associated in one study with approximately 50% greater risk for vertebral fracture (16). For both alendronate and zoledronate, discontinuation was associated with small (1% to 3%) but statistically significant greater decreases in BMD compared with continued use (19–21).

Evidence is insufficient from trials to determine whether bisphosphonate drug holidays reduce risk for rare events of ONJ, AFF, or other adverse events. Observational studies suggest that risk for incident AFF may decrease after initiation of drug holidays (22, 23).

In addition, studies generally had insufficient or low-strength evidence to assess effect modification by patient or clinical characteristics for drug holidays.

Drug Holidays for Other Medications

In general, holidays are not recommended for drugs other than bisphosphonates. In the FREEDOM trial of long-term denosumab, patients who discontinued treatment after at least 1 year had an increased rate of vertebral fracture after discontinuation (24), similar to the rate among those who never took the drug. Evidence is insufficient to compare the effects of denosumab drug holidays after different treatment durations. The reduced risk for AFF or ONJ after discontinuation is also unclear.

Long-term anabolic treatment of osteoporosis is not advised, so discontinuation after long-term use cannot be evaluated. The evidence suggests that the benefits of anabolic medications, denosumab, estrogen, and selective estrogen receptor modulators are quickly lost after discontinuation (25–27).

Current Gaps in Knowledge

There is insufficient empirical evidence on which to base recommendations regarding who should be considered for drug holidays, when to initiate them, the optimal duration, or the appropriate management of patients on drug holiday.

Research is needed on identifying patients at greatest risk for harms with long-term bisphosphonate use. A validated risk profile, including patient characteristics and treatment preferences in combination with clinical factors, is needed. There is also a need for improved understanding of pathogenesis underlying risk and the role of hip geometry and genetics in the risk for serious adverse events.

There is a need to determine the optimal initiation, duration, and other conditions of drug holidays. Whereas drug discontinuation is commonly a conscious decision made by patients and providers on the basis of clinical information, most evidence regarding drug holidays comes from clinical trials, where discontinuation occurred at arbitrary time points. Furthermore, the relevant period during which risk for AFF or ONJ might increase under bisphosphonates is unclear, and the appropriate timing and optimal duration of drug holidays is unknown. Without comparative evidence for alternative drug holiday durations, it is unclear what the fracture risk pattern is with discontinuation (especially over longer periods), how long benefits of bisphosphonate use might persist, or at what point the risk for harms might be minimized.

Sequencing or combining different classes of medications is a variation on drug holidays. This approach would shorten exposure to bisphosphonates and lessen potential harms. However, limited evidence exists on appropriate use of other medications, such as anabolic therapy, to complement bisphosphonate treatments. For instance, it is unclear whether treatment with anabolic drugs would be a safer alternative to bisphosphonate discontinuation. Similarly, the evidence is limited on the effectiveness of different sequencing of osteoporosis medications (for example, anabolics preceding antiresorptive agents) or their use in combination (for example, adding anabolics to bisphosphonates).

Patient and Clinician Barriers to Care

Effective drug therapies are only successful when the people who are at highest risk for fracture use them. In the case of osteoporosis, many people at greatest risk for fracture go undiagnosed. Among women at high risk for fracture, defined as those over 65 years of age and having at least 2 other fracture risk factors, only about one third reported treatment with osteoporosis medication (28). These rates are similar to those from another study, which found that only one third of patients prescribed osteoporosis medication fill their prescription, even when cost is not a factor (29). Among older adults in the United States who had a hip fracture not due to trauma or cancer, only 11% who were identified by U.S. Medicare claims and 13% identified by commercial claims filled any prescription for osteoporosis medication within 3 months after their fracture (30). Information about ODT use and adherence was not included in the systematic evidence review, so this report relied on material provided by workshop speakers.

Clinician Factors

Low rates of diagnosis and treatment probably stem from multiple clinician and patient factors. For the clinician, workshop speakers discussed problems with time, knowledge gaps, and appropriate systems in primary care. Inadequate time is most likely the biggest contributing factor to the lack of attention to osteoporosis among primary care physicians (31). Workshop speakers discussed how knowledge gaps may exist, but particularly about osteoporosis risk in relatively younger adults. In addition, communication about osteoporosis treatment between clinicians may lapse as patients transition from one setting to another after hospitalization. Several studies have discussed how the use of a hospital-based fracture liaison service (FLS) to coordinate care after a fracture may improve communication, resulting in better patient care (32). Specifically, potential benefits of greater case management at the time of hospital admission for a fracture include decreasing perioperative mortality as a consequence to expedited preoperative evaluation and decreased hospital length of stay (33). This coordinated care team may also increase the likelihood of screening tests and osteoporosis medication use (34).

Patient Factors

Patient factors include perceptions that osteoporosis is a normative consequence of aging or a process that occurs only among older adults; perceived drug ineffectiveness; medication side effects; or complex dosing regimens, medication cost, and poor education and health literacy (35, 36). Education-based interventions sometimes increase rates of medication prescriptions being filled, but not medication adherence 6 or 10 months later (37). Coaching, counseling, or educational interventions have been largely ineffective (38); the more effective FLS- and pharmacist-based interventions produce modest effects (39).

Patients often perceive medication risks as outweighing any possible benefits, particularly for the rare but severe side effects of bisphosphonates, including ONJ and AFF (40). In the decision-making literature, researchers find that people often overestimate their risk for rare adverse effects from receiving medication but tend to underestimate the likelihood of having a fracture because they exercise and take calcium (41). Treatment decisions should be a collaborative process between the patient and the provider, with discussion of such issues as the method, frequency, and duration of intake; medication cost; and consideration of benefits and risks.

Current Gaps in Knowledge

We need to identify the reasons why people have low rates of screening and adherence to medication, and we need to address these potential barriers. For example, more research is needed to understand how patients and providers rate the relative impact of a fracture on such aspects as mobility, social functioning, pain, independence, and mortality. Then we need to understand how to increase diagnostic efforts and long-term medication adherence for people who are at greatest risk for fracture.

The few successful interventions have yielded only modest outcomes. Time constraints for primary care physicians point to the need to develop new models for preventive care. Such models as case management teams and hospital-based liaison services exist, but randomized controlled clinical trials are needed to test their effectiveness. In addition, further research should tie the efficacy of ODT, currently assessed by fracture, more directly to the sequelae of fractures, such as changes in functional status, hospital stays, and pain. When we have information on these outcomes, such as how medication use after a fragility fracture is linked to future fractures or survival rates, we need to understand how to convey that information to patients so they can make more informed decisions about their care. In addition, the relative importance of certain benefits and side effects of medication use may vary by age, so age is an important factor to consider when examining motivation for diagnosis and treatment. Finally, more research is needed regarding the factors necessary for effective shared decision-making processes between patients and clinicians.

Conclusion

A body of high-quality evidence, primarily in postmenopausal white women, has established the general safety and effectiveness of ODT. Yet, this body of evidence has important gaps to guiding clinical management decisions. There are questions about who should be prioritized for treatment, when treatment should be initiated, which medication should be started first, how long treatment should be maintained, how treatment should be monitored, in what order treatments should be used, and whether drug holidays should be considered or implemented. Answers to these questions are needed to realize the population benefits from ODT.

Knowing who should be treated is hampered by gaps in the understanding of effect modification of the treatment benefits and harms, as well as by limits in the homogeneity of patients included in trials and studies. Gaps in our understanding of the uncommon side effects reported with bisphosphonates leave questions about which class of drugs should be used initially, when treatment should be started, how long treatment should be continued, whether interruptions in treatment would be beneficial, whether lower doses might be preferable, and whether sequencing drugs would be beneficial. Finally, there are questions on how best to implement many of these interventions in our complex health systems, taking into account patient and provider considerations affecting medication initiation and its continuation, especially in multimorbid adults and those in residential care.

Decisions about whether to prescribe ODTs will probably involve shared decision making, and the balance of risks and benefits will vary by patient. For people who are in a hospital for a fragility fracture, these decisions may involve a fracture liaison team that should coordinate with the primary care provider. Ideally, balancing risks and benefits would include estimates, not only of fracture rates, but also of future function, mobility, and other outcomes important to patients. The benefits relative to risks may differ in the setting of a recent fracture as opposed to primary prevention in a patient with no previous fracture. For some patients, the balance of benefits and risks will be favorable and many of those patients may opt for treatment. Some patients may weigh risks for harms more heavily and may choose to decline or defer treatment. In either case, the information used in shared decision making can be better informed by additional research addressing some of the research gaps noted above. This is reflected in our recommendations (Table).

Table. Summary of Workshop Panel Recommendations for Future Research to Advance the Field of Long-Term Osteoporotic Drug Therapy

Recommendations for Future Research

For existing and possible new treatments to optimize treatment duration, new research should make use of innovative research designs and approaches, including modeling studies. The regulatory framework should consider whether a broader array of trial designs should be permitted, including preference designs, sequential intervention designs, adaptive trial methodology, or innovative platform trials as used in cancer research, where the target of investigation is the disease and not the drug; end points should include fracture sequelae. Few observational studies have yet to apply causal inference methods and include fracture sequelae. Studies should include diverse populations that more closely match the characteristics of people experiencing osteoporotic fractures—including men, the spectrum of races and ethnicity, people with multiple comorbidities taking multiple medications, people in a variety of residential settings, and those with high fracture risk who do not meet criteria for osteoporosis. These trials should specify possible effect modifiers a priori. Future trials of new agents estimating efficacy should consider the ethics of placebo controls, given the safe, effective, approved ODTs that are available (comparative effectiveness trials), as well as standardized measures of uncommon side effects.

Concerns about AFF and ONJ may contribute to decisions about initiating and continuing treatment with bisphosphonates, and research should prioritize these complications. Studies should use standard case definitions for these complications and should estimate their incidence using specified methods for ascertainment and follow-up. Studies are needed on incidence by ethnicity, characterization of these complications, pathogenesis, risk factors and algorithms to predict risk, early detection, interventions to reduce their incidence (for example, improved oral hygiene), and their management if complications occur. Improving understanding and management of these complications could potentially mitigate an important barrier to bisphosphonate or denosumab use.

Drug holidays and sequential therapies have been suggested to reduce the incidence of these complications. Research should determine who is at greatest risk for adverse outcomes associated with long-term ODT, including but not limited to AFF and ONJ. Risks for harms should be considered along with the risk for osteoporotic fracture and patient preferences when deciding who may benefit from a drug holiday and who should continue medication use.

Consideration needs to be given to how drug holidays are implemented, including drug- and patient-specific determination of optimal timing, duration of holiday, and follow-up. Study of the efficacy of lower-dose bisphosphonate treatment to delay or prevent the need for drug holidays is warranted. Given the limitations of randomized, controlled studies to evaluate these questions, alternative study designs and existing data capturing the naturalistic discontinuation of ODT initiated by patients and providers, rather than discontinuation at arbitrary time points, should be used. Development of a consensus definition of “drug holiday” will aid in the collection of data and allow standardization in the evaluation of drug holiday effects.

Furthermore, guidance is needed for the appropriate follow-up and management of patients during drug holidays, including time frame for follow-up, screening measures, and reinitiation or substitution of medication after the drug holiday.

Similarly, the use of other pharmacologic therapies to supplement bisphosphonate treatment or replace bisphosphonates during drug holidays should be evaluated. Limited evidence suggests that sequencing ODTs may enhance the success, but the appropriate time frame, order, ODTs, and patient characteristics for sequential therapy are uncertain to maximize benefits and minimize drug exposure and risk for harms.

With respect to barriers to treatment, little evidence ties specific ODTs to long-term benefits in pain relief or function pre- or postfracture. Research addressing decision-making factors that predict who initiates treatment, who does not, and why will inform the relative importance of the factors weighed in these decisions. We currently know demographic factors related to adherence to ODTs, but less about attitudes and other appraisals influencing medication use. Adherence is low, and less is known on how to increase long-term medication use. More empirical studies, and particularly randomized, controlled trials, are needed to provide evidence on the efficacy of different management approaches, such as hospital-based FLS and other case management models.

Finally, research is needed as to the best context for shared decision making between patients and health care professionals. Results would clarify the type of relationship necessary for effective communication, and how inclusion of family members or other informal caregivers influence decision-making processes.

Aging of the population increases the prevalence of osteoporosis and its consequences. Although ODTs may have played a part in more recent reductions in fracture incidence, uncommon but potentially serious side effects have been associated with these treatments. Clinicians and patients need increased information on benefits and risks to inform shared decision making about the use of these treatments, taking into account patients' values and preferences. The research outlined above is urgently needed to advance prevention of osteoporosis-related mortality and morbidity.

References

Crandall
CJ
,
Newberry
SJ
,
Diamant
A
,
Lim
YW
,
Gellad
WF
,
Booth
MJ
,
et al
Comparative effectiveness of pharmacologic treatments to prevent fractures: an updated systematic review.
Ann Intern Med
2014
161
711
23
CrossRef

PubMed
Viswanathan
M
,
Reddy
S
,
Berkman
N
,
Cullen
K
,
Middleton
JC
,
Nicholson
WK
,
et al
Screening to prevent osteoporotic fractures: updated evidence report and systematic review for the US Preventive Services Task Force.
JAMA
2018
319
2532
51
PubMed
CrossRef

PubMed
Wysowski
DK
,
Greene
P
.
Trends in osteoporosis treatment with oral and intravenous bisphosphonates in the United States, 2002-2012.
Bone
2013
57
423
8
PubMed
CrossRef

PubMed
Lewiecki
EM
,
Wright
NC
,
Curtis
JR
,
Siris
E
,
Gagel
RF
,
Saag
KG
,
et al
Hip fracture trends in the United States, 2002 to 2015.
Osteoporos Int
2018
29
717
22
PubMed
CrossRef

PubMed
Jha
S
,
Wang
Z
,
Laucis
N
,
Bhattacharyya
T
.
Trends in media reports, oral bisphosphonate prescriptions, and hip fractures 1996-2012: an ecological analysis.
J Bone Miner Res
2015
30
2179
87
PubMed
CrossRef

PubMed
National Institutes of Health. Osteoporosis prevention, diagnosis, and therapy. National Institutes of Health Consensus Development Conference Statement. 27–29 March 2000. Accessed at https://consensus.nih.gov/2000/2000osteoporosis111html.htm on 27 March 2019.
Ortman JM. U.S. Population projections: 2012 to 2060. Presentation for the FFC/GW Brown Bag Seminar Series on Forecasting. Washington, DC: U.S. Census Bureau, U.S. Department of Commerce; 7 February 2013. Accessed at https://www2.gwu.edu/~forcpgm/Ortman.pdf on 27 March 2019.
Wright
NC
,
Looker
AC
,
Saag
KG
,
Curtis
JR
,
Delzell
ES
,
Randall
S
,
et al
The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine.
J Bone Miner Res
2014
29
2520
6
PubMed
CrossRef

PubMed
Nuti
R
,
Brandi
ML
,
Checchia
G
,
DiMunno
O
,
Dominguez
L
,
Falaschi
P
,
et al
Guidelines for the management of osteoporosis and fragility fractures.
Intern Emerg Med
2019
14
85
102
PubMed
CrossRef

PubMed
Agency for Healthcare Research and Quality. Pathways to Prevention (P2P). Workshop draft systematic evidence review: long-term drug therapy and drug holidays for osteoporosis fracture prevention. Accessed at https://prevention.nih.gov/research-priorities/research-needs-and-gaps/pathways-prevention-current/appropriate-use-drug-therapies-osteoporotic-fracture-prevention on 27 March 2019.
Committee on Practice Bulletins-Gynecology, The American College of Obstetricians and Gynecologists
ACOG practice bulletin n. 129. Osteoporosis.
Obstet Gynecol
2012
120
718
34
PubMed
CrossRef

PubMed
Fink
HA
,
MacDonald
R
,
Forte
ML
,
Rosebush
CE
,
Ensrud
KE
,
Schousboe
JT
,
et al
Long-term drug therapy and drug discontinuations and holidays for osteoporosis fracture prevention. A systematic review.
Ann Intern Med
2019. [Epub ahead of print]
Edwards
BJ
,
Bunta
AD
,
Lane
J
,
Odvina
C
,
Rao
DS
,
Raisch
DW
,
et al
Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project.
J Bone Joint Surg Am
2013
95
297
307
PubMed
CrossRef

PubMed
Cummings
SR
,
SanMartin
J
,
McClung
MR
,
Siris
ES
,
Eastell
R
,
Reid
IR
,
et al
FREEDOM Trial
Denosumab for prevention of fractures in postmenopausal women with osteoporosis.
N Engl J Med
2009
361
756
65
PubMed
CrossRef

PubMed
Bone
HG
,
Wagman
RB
,
Brandi
ML
,
Brown
JP
,
Chapurlat
R
,
Cummings
SR
,
et al
10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension.
Lancet Diabetes Endocrinol
2017
5
513
23
PubMed
CrossRef

PubMed
Feldstein
AC
,
Black
D
,
Perrin
N
,
Rosales
AG
,
Friess
D
,
Boardman
D
,
et al
Incidence and demography of femur fractures with and without atypical features.
J Bone Miner Res
2012
27
977
86
PubMed
CrossRef

PubMed
Adler
RA
.
Management of endocrine disease: atypical femoral fractures: risks and benefits of long-term treatment of osteoporosis with anti-resorptive therapy.
Eur J Endocrinol
2018
178
R81
7
PubMed
CrossRef

PubMed
Qaseem
A
,
Forciea
MA
,
McLean
RM
,
Denberg
TD
.
Clinical Guidelines Committee of the American College of Physicians
Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians.
Ann Intern Med
2017
166
818
39
CrossRef

PubMed
Black
DM
,
Schwartz
AV
,
Ensrud
KE
,
Cauley
JA
,
Levis
S
,
Quandt
SA
,
et al
FLEX Research Group
Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.
JAMA
2006
296
2927
38
PubMed
CrossRef

PubMed
Black
DM
,
Reid
IR
,
Cauley
JA
,
Cosman
F
,
Leung
PC
,
Lakatos
P
,
et al
The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT).
J Bone Miner Res
2015
30
934
44
PubMed
CrossRef

PubMed
McClung
M
,
Miller
P
,
Recknor
C
,
Mesenbrink
P
,
Bucci-Rechtweg
C
,
Benhamou
CL
.
Zoledronic acid for the prevention of bone loss in postmenopausal women with low bone mass: a randomized controlled trial.
Obstet Gynecol
2009
114
999
1007
PubMed
CrossRef

PubMed
Adams AL, Li BH, Ryan DS, Geiger EJ, Dell RM, Black DM. Do drug holidays reduce atypical femur fracture risk? Results from the Southern California Osteoporosis Cohort Study (SOCS). Presented at the 2018 American Society for Bone and Mineral Research Annual Meeting; 28 September to 1 October 2018; Montreal, Quebec, Canada. Abstract 1005.
Black DM, Geiger EJ, Li BH, Ryan DS, Dell RM, Adams AL. Bisphosphonate use and risk of AFF varies by pre-treatment BMD level: results from the Southern California Osteoporosis Cohort Study (SOCS). Presented at the 2018 American Society for Bone and Mineral Research Annual Meeting; 28 September to 1 October 2018; Montreal, Quebec, Canada. Abstract 1007.
Cummings
SR
,
Ferrari
S
,
Eastell
R
,
Gilchrist
N
,
Jensen
JB
,
McClung
M
,
et al
Vertebral fractures after discontinuation of denosumab: A post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension.
J Bone Miner Res
2018
33
190
198
PubMed
CrossRef

PubMed
Cohen
A
,
Kamanda-Kosseh
M
,
Recker
RR
,
Lappe
JM
,
Dempster
DW
,
Zhou
H
,
et al
Bone density after teriparatide discontinuation in premenopausal idiopathic osteoporosis.
J Clin Endocrinol Metab
2015
100
4208
14
PubMed
CrossRef

PubMed
McClung
MR
,
Wagman
RB
,
Miller
PD
,
Wang
A
,
Lewiecki
EM
.
Observations following discontinuation of long-term denosumab therapy.
Osteoporos Int
2017
28
1723
32
PubMed
CrossRef

PubMed
Tsourdi
E
,
Langdahl
B
,
Cohen-Solal
M
,
Aubry-Rozier
B
,
Eriksen
EF
,
Guañabens
N
,
et al
Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS.
Bone
2017
105
11
7
PubMed
CrossRef

PubMed
Guggina
P
,
Flahive
J
,
Hooven
FH
,
Watts
NB
,
Siris
ES
,
Silverman
S
,
et al
GLOW Investigators
Characteristics associated with anti-osteoporosis medication use: data from the Global Longitudinal Study of Osteoporosis in Women (GLOW) USA cohort.
Bone
2012
51
975
80
PubMed
CrossRef

PubMed
Reynolds
K
,
Muntner
P
,
Cheetham
TC
,
Harrison
TN
,
Morisky
DE
,
Silverman
S
,
et al
Primary non-adherence to bisphosphonates in an integrated healthcare setting.
Osteoporos Int
2013
24
2509
17
PubMed
CrossRef

PubMed
Kim
SC
,
Kim
MS
,
Sanfélix-Gimeno
G
,
Song
HJ
,
Liu
J
,
Hurtado
I
,
et al
Use of osteoporosis medications after hospitalization for hip fracture: a cross-national study.
Am J Med
2015
128
519
26
PubMed
CrossRef

PubMed
Yarnall
KS
,
Pollak
KI
,
Østbye
T
,
Krause
KM
,
Michener
JL
.
Primary care: is there enough time for prevention?
Am J Public Health
2003
93
635
41
PubMed
CrossRef

PubMed
Solomon
DH
,
Patrick
AR
,
Schousboe
J
,
Losina
E
.
The potential economic benefits of improved postfracture care: a cost-effectiveness analysis of a fracture liaison service in the US health-care system.
J Bone Miner Res
2014
29
1667
74
PubMed
CrossRef

PubMed
Swart
E
,
Vasudeva
E
,
Makhni
EC
,
Macaulay
W
,
Bozic
KJ
.
Dedicated perioperative hip fracture comanagement programs are cost-effective in high-volume centers: an economic analysis.
Clin Orthop Relat Res
2016
474
222
33
PubMed
CrossRef

PubMed
Majumdar
SR
,
Johnson
JA
,
Bellerose
D
,
McAlister
FA
,
Russell
AS
,
Hanley
DA
,
et al
Nurse case-manager vs multifaceted intervention to improve quality of osteoporosis care after wrist fracture: randomized controlled pilot study.
Osteoporos Int
2011
22
223
30
PubMed
CrossRef

PubMed
Lee
S
,
Glendenning
P
,
Inderjeeth
CA
.
Efficacy, side effects and route of administration are more important than frequency of dosing of anti-osteoporosis treatments in determining patient adherence: a critical review of published articles from 1970 to 2009.
Osteoporos Int
2011
22
741
53
PubMed
CrossRef

PubMed
Hiligsmann
M
,
Bours
SP
,
Boonen
A
.
A review of patient preferences for osteoporosis drug treatment.
Curr Rheumatol Rep
2015
17
61
PubMed
CrossRef

PubMed
Shu
AD
,
Stedman
MR
,
Polinski
JM
,
Jan
SA
,
Patel
M
,
Truppo
C
,
et al
Adherence to osteoporosis medications after patient and physician brief education: post hoc analysis of a randomized controlled trial.
Am J Manag Care
2009
15
417
24
PubMed
PubMed
Jaleel
A
,
Saag
KG
,
Danila
MI
.
Improving drug adherence in osteoporosis: an update on more recent studies.
Ther Adv Musculoskelet Dis
2018
10
141
9
PubMed
CrossRef

PubMed
Solomon DH. Osteoporosis improvement across the provider spectrum: implementation and economics [slide presentation]. National Institutes of Health Pathways to Prevention Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention. 30-31 October 2018. Accessed at https://prevention.nih.gov/research-priorities/research-needs-and-gaps/pathways-prevention-current/appropriate-use-drug-therapies-osteoporotic-fracture-prevention on 27 March 2019.
Cipriani
C
,
Pepe
J
,
Minisola
S
,
Lewiecki
EM
.
Adverse effects of media reports on the treatment of osteoporosis.
J Endocrinol Invest
2018
41
1359
64
PubMed
CrossRef

PubMed
Silverman
S
,
Gold
DT
.
Medication decision-making in osteoporosis: can we explain why patients do not take their osteoporosis medications?
Curr Osteoporos Rep
2018
16
772
4
PubMed
CrossRef

PubMed

Position Papers |2 July 2019

National Institutes of Health Pathways to Prevention Workshop: Research Gaps for Long-Term Drug Therapies for Osteoporotic Fracture Prevention Free

Abstract

Evidence Regarding Benefits and Harms of Long-Term ODTs

Current Gaps in Knowledge

Drug Holidays

Bisphosphonate Drug Holidays

Drug Holidays for Other Medications

Current Gaps in Knowledge

Patient and Clinician Barriers to Care

Clinician Factors

Patient Factors

Current Gaps in Knowledge

Conclusion

Table. Summary of Workshop Panel Recommendations for Future Research to Advance the Field of Long-Term Osteoporotic Drug Therapy

Recommendations for Future Research

References

Table. Summary of Workshop Panel Recommendations for Future Research to Advance the Field of Long-Term Osteoporotic Drug Therapy

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Position Papers |2 July 2019

National Institutes of Health Pathways to Prevention Workshop: Research Gaps for Long-Term Drug Therapies for Osteoporotic Fracture Prevention Free

Abstract

Evidence Regarding Benefits and Harms of Long-Term ODTs

Current Gaps in Knowledge

Drug Holidays

Bisphosphonate Drug Holidays

Drug Holidays for Other Medications

Current Gaps in Knowledge

Patient and Clinician Barriers to Care

Clinician Factors

Patient Factors

Current Gaps in Knowledge

Conclusion

Table. Summary of Workshop Panel Recommendations for Future Research to Advance the Field of Long-Term Osteoporotic Drug Therapy

Recommendations for Future Research

References

Table. Summary of Workshop Panel Recommendations for Future Research to Advance the Field of Long-Term Osteoporotic Drug Therapy

This feature is available only to Registered Users

0 Comments

See Also

Related Articles

Journal Club

Related Point of Care

Related Topics

PubMed Articles

Content

Information For

Services

Awards and Cover

Other Resources

Follow Annals On

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