Gaps in evidence on treatment of male osteoporosis: a Research Agenda

Abstract Objective To identify key research gaps regarding medication therapy to prevent osteoporotic fractures in men. Data sources Articles from the peer-reviewed literature containing empirical studies of the use of medication therapy for fracture prevention in men, either in clinical trials or observational studies. Study selection and data extraction We searched PubMed with search terms including “osteoporosis AND medication therapy management”. We read all articles to ensure that they were indeed empirical studies of our topic. For each included study, we searched for all articles in the bibliography, all articles that cited the article, and all related articles, using these functions in PubMed. Data synthesis We have identified six research gaps that could inform the more rational, evidence-based treatment of male osteoporosis. Specifically, among men, we lack key information about: (1) whether treatment can prevent clinical fractures, (2) rates of side effects and complications of therapy, (3) the role of testosterone in treatment, (4) the comparative effectiveness of different therapeutic regimens, (5) role of drug holidays for those receiving bisphosphonates and sequential therapies, and (6) effectiveness of therapy for secondary prevention. Relevance to patient care and clinical practice Addressing these six topics should be key goal for the next decade of research on male osteoporosis.

someone has been diagnosed with osteoporosis, beyond the basic lifestyle interventions, what treatment can be offered to them, and how effective is it?Our answers to these questions, for a male, are still largely unknown.The purpose of this review is to clarify what we don't know, which will help set an agenda for what can be done to fill in these knowledge gaps.

Male osteoporosis is likely very different from female osteoporosis
There are some common risk factors that are shared between male and female osteoporosis, including smoking, alcohol, and the negative effects of glucocorticoid use on bone health [6,7].However, male osteoporosis may be quite different from female osteoporosis, and may behave quite differently.Males are exposed to much higher levels of testosterone than women throughout their lives, and have lower but non-trivial levels of estrogen as well [8].In fact, estrogen has an extremely important role in male bone health and in predicting fractures [9][10][11].
Studies have shown that while osteoporosis is characterized by disordered bone among both men and women, it is disordered in different ways [12].Further, the pace of bone loss and the sites of loss is different in men versus women [13].Specifically, women tend to lose bone at a younger age and at a more rapid pace and more often have fractures at vertebral sites compared to men [14].In addition, the skeletal integrity of male cortical bone is different, and the crosssectional area appears to be greater among males; these differences, and changes in these parameters over time, seem to mediate the risk of osteoporotic fractures in men [15].Given these facts, we cannot necessarily expect that what we know about osteoporosis from our studies of women will be directly applicable to men.This means that we need dedicated studies to understand how best to treat osteoporosis in men, but we have only limited data from such studies to inform our practice.

Goals of this review
This review will briefly focus on six major topics about the treatment of osteoporosis in male patients, which are needed to guide clinical practice.Several adjacent topics also require better evidence, such as how best to approach screening and diagnosis of osteoporosis among men.While these other topics are also important, they are outside the scope of this review.This review is focused on therapeutic management in a patient who already has a diagnosis of osteoporosis.We identified six main unresolved issues under this topic, as we will discuss below.
There have been previous reviews of how clinicians should approach the management of osteoporosis in male patients [16], both for primary and secondary prevention [17].These reviews offer excellent advice.However, these reviews also emphasized that we are missing important evidence to guide our practice.Clarifying these evidence gaps more precisely is the topic of the present review.

Search strategy/methods
Our goal was to identify all original empirical studies related to medication therapy for fracture prevention in men, including clinical trials and observational studies.We searched Medline, using search terms including "osteoporosis AND medication therapy management".After identifying the articles, we examined them to determine if they described the use of medications for primary or secondary prevention of fractures in men.We used the bibliographies of articles identified to find additional articles.We also searched for related articles on each of the articles we included, using the "find related articles" function in Medline.Finally, we used the "find citing articles" function in Medline for all the articles we included.

Does treatment of male osteoporosis prevent clinical fractures?
In contrast to the relatively large body of work on the clinical benefits of therapies to reduce fractures in women [18], there have been relatively few studies that focused on fracture reduction in men.A recent meta-analysis by Nayak and Greenspan regarding treatment efficacy in men was based on 4,868 participants -the total number of men who were found to have participated in any qualifying randomized studies of treatment for osteoporosis [19].This meta-analysis generally found that bisphosphonate treatment is effective compared to placebo in preventing vertebral fractures (Rate Ratio 0.37) and non-vertebral fractures (Rate Ratio 0.60) [19].However, similar conclusions in women are based on many times as many trial participants.For example, a meta-analysis by Crandall and colleagues included tens of thousands of women for each of the medications studied, and some of the studies cited included more women than the entire meta-analysis of men combined [18].
A few short-term studies of up to 2 years in men did report fracture reduction.A randomized doubleblind placebo-controlled trial by Orwoll and colleagues evaluated the efficacy of 10 mg of alendronate daily among 146 men with osteoporosis, compared to 95 men who received a placebo [20].The study found that alendronate was associated with increased bone mineral density (BMD).Alendronate prevented radiologically-detected vertebral fractures (0.8% vs. 7.1%, p ¼ 0.02) and was associated with a statistically significant decrease in loss of height (0.6 mm vs. 2.4 mm, p ¼ 0.02).The study did not detect a statistically significant difference in clinically apparent (painful) vertebral fractures (0.7% vs. 3.2%, p ¼ 0.30) or non-vertebral fractures (4.1% vs. 5.3%, p ¼ 0.80).Similar results were noted in a larger 24-month double-blind randomized trial of zoledronic acid, another bisphosphonate on BMD and vertebral fractures among men with osteoporosis [21].
There have been other studies of bisphosphonates in men, including an open-label randomized study of risedronate, which had follow-ups at one and two years [22,23].At the two-year follow-up, there was a reduced rate of radiologic vertebral fractures in the risedronate group (9.2% vs. 23.6%,p ¼ 0.003), improved bone mineral density, and a reduction in non-vertebral fractures (11.8% vs. 22.3%, p ¼ 0.03).Risedronate recipients also had less loss of height (3.5 mm vs. 8.5 mm, p < 0.001) and less back pain.The study was not adequately powered to detect a reduction of hip fractures.
We also found a large observational study of bisphosphonate therapy that included some men [24].However, while this study of 24,571 patients included 12% men, results were not reported separately for the male subset, and therefore little can be concluded from this study about the effectiveness of bisphosphonate therapy for men in particular.
There have also been studies of non-bisphosphonate medications for men, especially teriparatide and denosumab.In a randomized trial, teriparatide was shown to increase BMD, and to reduce radiologic vertebral fractures by about half, among men with osteoporosis -with these benefits persisting for up to 30 months after treatment cessation [25,26].In another randomized trial, denosumab treatment was shown to increase BMD and maintained reductions in bone absorption at 24 months [27].A trial of abaloparatide in men has reported final results [28], and on the basis of these results, abaloparatide has been FDA-approved for use in men.However, while this trial established an effect on BMD, a direct effect on fractures was not established.

What is the role of testosterone therapy for treating osteoporosis?
Testosterone is covered separately from other therapies (e.g.bisphosphonates, teriparatide) because many men receive testosterone for many other reasons besides osteoporosis [29].Testosterone is recommended for men with hypogonadism and signs and symptoms characteristic of hypogonadism, such as loss of muscle mass [30][31][32].A large number of studies have shown that testosterone replacement therapy can increase bone mineral density [33][34][35][36][37][38][39][40][41][42][43][44][45][46], although no study has demonstrated that it prevents clinical fractures.The main mechanism of action is thought to be the direct activation of osteoblasts to increase bone production [47].Testosterone could theoretically be used for men who have osteoporosis without hypogonadism (i.e.eugonadal men).The most clinically relevant use of testosterone would be for men who have proven hypogonadism and osteoporosis.For these men, testosterone could theoretically accomplish two goals at once.However, the efficacy of testosterone to prevent fractures remains unproven, while other options such as bisphosphonates have relatively strong proof of benefit.It also is not known whether testosterone could be more effective for fracture prevention when given in combination with other medications, or possibly in sequence with other medications.In short, the place of testosterone therapy in the clinical management of male osteoporosis contains many unknowns.

What are the rates of side effects and complications from osteoporosis treatment in males? Which patients are at highest risk?
We know from studies of women that there are adverse events and side effects with osteoporosis medications.The best-understood class of medications is bisphosphonates.We have the most experience with this drug class, both due to having used it for a quarter century and among millions of patients.Adverse events from bisphosphonates include extremely rare but serious events (atypical fractures, jaw osteonecrosis), as well as more common events (arthralgias from oral and IV bisphosphonates, and esophageal symptoms from oral bisphosphonates) [48][49][50][51].We also have some limited evidence about adverse events when other medications are used.For example, denosumab has been linked with atypical femoral fractures in women [52].
While more remains to be learned about these events in women, we know even less about the safety of osteoporosis treatment in men, and there may be important differences.Increased risk of atypical femoral fracture from bisphosphonates has also been noted in men in a retrospective study [53].Further, evidence suggests that these atypical femoral fractures may be related to increased treatment duration and that the risk of atypical femoral fractures from bisphosphonates decreases rapidly after cessation of treatment [54].We know even less about adverse events with medication classes other than bisphosphonates, and this too will require study.In addition, there may be some men who are at higher risk of such common or rare adverse events than the general population of men with osteoporosis; this also remains to be elucidated.A better understanding of the risks of common and uncommon adverse events would improve decision-making about who would benefit most from therapy.

What is the comparative effectiveness of treatments for male osteoporosis?
Comparative effectiveness is a topic that is difficult to study because medications are almost always studied one at a time and are compared to placebo, not to each other [55].To the extent that we eventually show that more than one medication is effective for preventing osteoporotic fractures in men, it will be important to find out if one of the medications is more effective than another, or possibly only more effective for a specific subset of patients.For now, we mainly depend on network meta-analyses [56].We also lack direct head-to-head medication comparisons for the treatment of osteoporosis in women, but this remains an important topic in men as well.

What is the impact of drug holidays and sequential therapies on safety and efficacy of bisphosphonate treatment?
The idea of drug holidays is only germane to bisphosphonate therapy, and not to therapy with other agents.However, since bisphosphonates are the mainstay of our treatment of osteoporosis, this is an important topic.Because bisphosphonates intercalate into the bone matrix, their duration of action may far outlast their serum half-life.Also, concerns that longterm bisphosphonate use might predispose patients to adverse events, such as atypical femoral fractures and osteonecrosis of the jaw have led to suggestions to pause bisphosphonate treatment after a certain number of years, and to restart it later, or to stop it altogether [57].The expectation with the drug holiday is that this could achieve similar clinical benefits while minimizing side effects and the need to take medication [57].
There are in fact some empirical studies demonstrating the efficacy of this approach -but only among women [58,59].Specifically, pausing alendronate for 5 years and zoledronate for 3 was associated with a greater risk for vertebral fracture [60], but not nonvertebral or hip fracture in post-menopausal women [61].Current guidelines state that for women who are not at high fracture risk, a drug holiday of 2-3 years can be considered after 3-5 years of bisphosphonate treatment, with periodic reassessment [56].In contrast to bisphosphonates, drug holidays are not recommended for denosumab, as bone loss increases rapidly after discontinuation, which may increase the risk for vertebral fractures [62].
In contrast, the optimal duration of treatment in men has not been determined, and no trials of drug holidays have been conducted in men [63].Further, no studies have been conducted on the effectiveness of sequencing of different therapies (e.g.denosumab following bisphosphonates) among either men or women [64].These strategies could represent another variation on drug holidays to help reduce potential harm and exposure to bisphosphonates while maximizing effectiveness [64].Because osteoporosis may be fundamentally different in men than in women, we need dedicated studies of the impact of drug holidays among men, rather than simply relying upon what we have learned about women.

What is the effectiveness of medication therapy for secondary prevention?
All of the above questions dealt with primary prevention -that is, preventing a first fracture among men diagnosed with osteoporosis.Men are more likely to be undertreated than women with medication after an osteoporotic fracture (secondary prevention) [65][66][67][68][69][70].This is concerning, as men are twice as likely to die within a year after a hip fracture compared to women [71].But how should we treat these men whose osteoporosis becomes apparent only through experiencing a fracture?Logic would dictate that secondary prevention would have a better risk-benefit ratio than primary prevention, because of the higher absolute risk of events.
To our knowledge, there has been one large empirical study focused solely on secondary prevention in men with osteoporosis [72].In this study, approximately 2000 men who had sustained an osteoporotic hip fracture were randomized to 5 mg of zoledronic acid yearly vs. placebo.The treatment group in this study had fewer clinical fractures, clinical vertebral fractures, and non-vertebral fractures -all statistically significant differences with approximately 30% relative risk reduction.There were no differences in adverse events, including atypical fractures, jaw osteonecrosis, or renal or cardiovascular events.Importantly, there was also a 30% reduction in all-cause mortality in the treatment group.
In addition to this study, some other studies also contained men who were treated for both primary and secondary prevention of fractures.For example, the study by Ringe, et al. discussed above, included men receiving risedronate for both primary and secondary prevention [22,23].However, the results were not presented separately for these two groups, limiting what we can learn about secondary prevention in particular.

Agenda for future research
Much remains to be learned about primary and secondary prevention among men with osteoporosis.This review has briefly explored six major questions that remain unanswered, and that could inform how we approach the treatment of osteoporosis among men.Ideally, we would have evidence from randomized trials of men with osteoporosis, which are long overdue.However, randomized trials take years to conclude and are very expensive [73].
It is therefore also important to consider how highquality observational studies could inform clinical practice in our management of male osteoporosis.Observational studies can have important advantages -they can be conducted relatively quickly, they can have relatively low cost, they can involve large populations and thus have the potential to detect rare events, and they may in some ways be more generalizable than randomized trials -because their populations are more representative [74].The advantages of randomized trials are also well-known, especially their ability to control for both observed and unobserved confounders, which has led to the justified emphasis on using them as the mainstay of clinical evidence to guide practice [75].However, we think that high-quality observational studies of men with osteoporosis may be preferable to continuing to rely on evidence from clinical trials among women.
Therefore, we recommend high-quality observational studies be considered to fill critical knowledge gaps regarding the optimal treatment and management of osteoporosis in men.Such studies could start by trying to address the issues we have set forth in this article.While randomized trials would be better in some ways, and should also proceed, this will take years and would usually depend on someone having the financial incentive to run such a trial.In the interim, it may be preferable to rely on evidence from high-quality observational studies of men with osteoporosis than to extrapolate from interventional studies of women.There are many important things that we do not know about how best to manage osteoporosis in men.It is hoped that this article will help spur us to fill in some of these knowledge gaps in the near future.