Secondary fracture prevention is good, avoiding the first fracture, better still









Maria Luisa BRANDI, MD, PhD
Full Professor of Endocrinology
Department of Surgery and Translational Medicine
University of Florence
Florence, ITALY

Secondary fracture prevention is good, avoiding the first fracture, better still


by M. L . Brandi, Italy



Osteoporosis will continue to be a growing burden as the population keeps getting older. Although awareness of osteoporosis is increasing, osteoporosis remains largely underdiagnosed and undertreated. In recent years, several guidelines have been developed for the diagnosis, prevention, and treatment of osteoporosis. Diagnostic tools, mainly based on densitometric measurement, are widely available and today efforts are being made to design specific tools for risk assessment based on the specific characteristics of a given population. Also, the usefulness of physical activity, calcium intake, and vitamin D administration as key players in preventing bone loss in the elderly has been fully demonstrated. Several drugs with different mechanisms of action on bone remodeling have been developed in the past two decades, all being able to prevent the risk of fracture. All of this, together with the recognized burden of the “fracture cascade,” makes it imperative to put in place interventions aiming to prevent the first fracture (primary prevention). However, osteoporosis drug reimbursement is mostly limited to preventing the fracture(s) that follow the first fracture (secondary prevention). But this recommendation is not followed by doctors, as in the majority of fracture cases the corresponding best practices are not applied. This article looks at how best to use diagnosis, risk assessment, prevention, and management of osteoporosis in primary prevention so as to avoid the first fracture..

Medicographia. 2014;36:192-196 (see French abstract on page 196)



Osteoporosis, literally “porous bone,” is a metabolic bone disorder characterized by fragile bone, with consequent fractures that occur spontaneously or as a result of minor trauma. However, even though the disease has been recognized for many years, the conceptual description of postmenopausal osteoporosis was formulated only less than 20 years ago by the World Health Organization (WHO), as a condition characterized by reduced bone mass, disruption of bone architectural features, and an increased risk of fracture.1 The WHO Report made it possible through the measurement of a quantifiable diagnostic measurement— bone mineral density (BMD)—to screen for osteoporosis in postmenopausal women, recognizing bone fragility as a defined condition affecting over 75 million people in Europe, the United States, and Japan.1 The operational definition of osteoporosis is based on the standard deviations (SDs) by which an individual’s femoral hip BMD, measured by dual energy x-ray absorptiometry (DXA), differs from the mean value expected in young healthy subject of the same sex (T-score). In men and women, osteoporosis is diagnosed if the T-score is less than or equal to –2.5 SD.2 This does not preclude the use of measurements at other skeletal sites by different technologies in clinical practice. Because the values of BMD in the young healthy population are normally distributed and bone loss occurs with advancing age, the prevalence of osteoporosis increases with age; this was shown in Sweden, where approximately 6% of men and 21% of women aged between 50 and 84 years were classified as having osteoporosis.3

Although the diagnosis of osteoporosis relies on the quantitative measurement of BMD, a variety of nonskeletal factors contribute to the risk of low energy fracture.4 In analogy with other multifactorial chronic diseases, such as hypertension, a distinction needs to be made between the use of BMD for diagnosis and for risk assessment. Thus, FRAX® (Fracture Risk Assessment tool), a computer-based algorithm was developed to calculate the 10-year probability of major osteoporotic fracture (hip, clinical spine, humerus, or wrist fracture) and the 10-year probability of hip fracture (http://www.shef.ac. UK/FRAX).5,6 The use of clinical risk factors—age, body mass index, prior fragility fracture, parental history of hip fracture, current tobacco smoking, ever use of long-term oral glucocorticoids, rheumatoid arthritis, other causes of secondary osteoporosis, and alcohol consumption—improves the sensitivity of fracture prediction without having any adverse effects on specificity.6 As fracture probability is characterized by marked geographic differences, FRAX® is calibrated to those regions where the epidemiology of fractures and death is known.7

Burden of disease

The worldwide estimated annual number of common osteoporotic fractures in men and women is of more than 8.9 million— approximately 1000 per hour.8 In Sweden, the remaining lifetime risk of sustaining a major osteoporotic fracture at the age of 50 years is 46.4% in women and 22.4% in men, with the vast majority of osteoporotic fractures occurring in elderly women.8 The worldwide incidence of hip fracture shows large differences and this is probably true also for other fragility fractures, with a greater variation among regions than between sexes within a country.8

The global burden of osteoporosis can be quantified by disability- adjusted life years (DALYs). In the year 2000 the worldwide DALYs lost for common osteoporotic fractures was 5.8 million, accounting for 0.83% of the global burden of noncommunicable diseases.8 Due to the increased longevity in developed and underdeveloped countries, the frequency of osteoporotic fractures is increasing in several regions and it is expected that it will more than quadruple over the next 25 years.9

In 2010, the total monetary osteoporosis burden in the EU5 (France, Germany, Italy, Spain, UK) was estimated at €29.3 billion, with approximately 70% of the total costs incurring in individuals older than 74 years.8 The burden of fractures, expressed as the sum of total costs and the value of Quality Adjusted Life Years (QALYs), was estimated at €736 billion in the EU5, with a financial burden for osteoporosis exceeding that of migraine, stroke, multiple sclerosis, and Parkinson’s disease.8

Osteoporosis is a major noncommunicable disease and is set to increase markedly in the future. The ultimate goal of osteoporosis management is to reduce the risk of future fractures; but is every effort put in place to act against this epidemic? The answer is no, as only a minority of patients at high fracture risk are identified and treated.10,11 There is therefore an urgent need to assess best practices in the prevention and treatment of osteoporosis.

Levels of prevention of osteoporotic fractures

In the last twenty years, there have been enormous advances in our understanding of the many factors that contribute to fracture risk, and in elucidating the genetic, molecular, and cellular mechanisms that regulate bone metabolism, growth, and involution during the course of life. Based on this knowledge, we now have the ability to identify in a more efficient and timely manner those individuals that have a high fracture risk, and thus be in the position to start them on preventive strategies that have been proven to be effective in reducing the risk of fracture.

The different levels of osteoporosis prevention are usually defined based on the reimbursement policy for antifracture drugs, with primary and secondary prevention being the pharmacological intervention taking place before and after a fragility fracture, respectively. However, when aiming to reduce the impact of bone fragility, we should consider factors other than just pharmacological therapy, including a healthy lifestyle. It is therefore urgent to define levels of intervention for bone fragility.


Table I
Table I. Levels of prevention for fragility fractures.


In an attempt to redefine the prevention of low trauma fractures in absolute terms, we should consider three levels of action: primary, secondary, and tertiary prevention (Table I).12 Primary prevention should encompass all the interventions used in the general population in order to reduce the fracture risk in an individual. These typically include adequate daily calcium intake, regular physical activity, adequate circulating concentrations of vitamin D, avoiding smoking, and limiting alcohol intake. The aim of secondary prevention should be the early recognition of an individual’s fracture risk in at-risk populations (ie, postmenopausal and secondary osteoporosis).

Measurement of BMD and FRAX® risk calculation are classical approaches used to quantify the fracture risk. Tertiary prevention would be for patients who have already sustained one or more fragility fractures. These patients should be assisted with pharmacological, surgical, and rehabilitation measures.

While there are significant quantitative data available to indicate that primary prevention is possible for osteoporosis and fragility fractures, as with other common chronic diseases, it may not be easy—nor quick—to reach this goal. This should not discourage us from taking a path that could lead to important results in the future by starting to educate the younger population today (ie, it is estimated that a 5% increase in bone at the end of bone development could translate into a 30% reduction of all fracture events in old age).13 However, despite the clear value of a healthier lifestyle in the primary prevention of osteoporosis, large population studies aiming to show the efficacy and economic efficiency of this approach are still lacking.

Considering the availability of both clinical and instrumental diagnostic tools for the recognition of the risk of fragility fractures, it should be possible to apply this knowledge to secondary prevention measures. The measurement of BMD is the only aspect of fracture risk that can be readily measured in clinical practice, and forms the cornerstone for the general management of osteoporosis, being used for diagnosis, risk prediction, the selection of patients for treatment, and monitoring of patients on treatment.14 However, worldwide differences exist among different countries on the availability of DXA, regarding its reimbursement and the practical use of densitometry measurements for drug reimbursement.8 Even though the current version does not incorporate fall-related risk factors (fall being a well-recognized strong risk factor), FRAX® is a well-validated tool that can be easily applied in clinical practice, widening the access to the assessment of fracture risk. Its application in clinical practice means that intervention thresholds should be based on fracture probability.8 It is clear that primary medicine needs to have a key role in the battle against fractures by contributing to the identification of subjects at risk.

While tertiary prevention is considered a necessary intervention, only a small number of the patients that are hospitalized for a fragility fracture are offered an appropriate diagnostic and therapeutic path after discharge, in spite of the high risk of recurrence that is typical in these patients.15 On the other hand, less than half of the patients that start a pharmacological treatment adhere to their medical and therapy regimen after one year, thus generating unacceptable system inefficiency and nullifying the chance of a cost-effective intervention.16 These two issues may seem simple; however, they share the need for a common approach from a cultural and organizational point of view, through the development of true “Fracture Units” to avoid the fragmentation of interventional measures. General practitioners may be in the best position to plan a therapeutic regimen and motivate their patients to adhere to the chosen medication.





These are interesting observations because they present a different perspective of osteoporosis prevention strategies. However, as indicated in national and international guidelines, pharmacological intervention is “primary” when treatment is prescribed to patients before the first fragility fracture and “secondary” when the patients have already experienced a spontaneous or low-trauma fracture. The question is: would it not be preferable to intervene prior to the occurrence of a fragility fracture? Examples of early intervention will be discussed below.

Prevention and treatment of osteoporosis during early postmenopause

One of the most important health issues for women entering the menopause is the threat of the development of osteoporosis and the consequent fractures, as it has been estimated that the average woman will lose up to 10% of her bone mass during the first 5 years of the menopause. Women commonly experience a phase of rapid bone loss that begins approximately 2 to 3 years before cessation of menses and continues for up to 3 or 4 years postmenopause.17 Although many factors are known to be associated with osteoporotic fractures, a large number of women do not have their bone density tested and few are prescribed therapy. Consequently, several women do not receive a diagnosis of osteoporosis until a fracture occurs.

To further complicate this scenario, a number of findings clearly suggest that the current BMD screening procedures do not identify the majority of younger postmenopausal women who subsequently experience a fracture.18 These facts underscore the need for identification of specific risk factors that should be monitored in addition to BMD for a more aggressive clinical management of osteoporosis in early postmenopausal women. Early intervention would enable these women to maintain or increase their bone mass and thereby reduce their fracture risk.

Nonpharmacological treatment options should be used as first-line intervention in low-risk patients and in conjunction with therapy in high-risk patients. For many years, hormone therapy was viewed as an appropriate strategy for the prevention of postmenopausal bone loss. However, because the risks of adverse events outweigh the potential benefits, prolonged use of hormonal therapy is no longer recommended.19

In recent years, new treatment strategies have become available to prevent and treat osteoporosis.20 Subanalyses within controlled clinical trials have shown that all the antifracture drugs are effective for the treatment of osteoporosis in postmenopausal women of all ages, with all drugs showing improvements in BMD and bone turnover markers.7 Moreover, in the EPIC study (Early Postmenopausal Intervention Cohort study), the largest and longest randomized controlled trial examining the effects of an antifracture drug in the prevention of postmenopausal osteoporosis, alendronate effectively normalized bone resorption and increased and maintained BMD over 6 years.21 Using BMD scores, rates of bone turnover, and risk-based diagnostic criteria as part of the decision to initiate therapy may allow for the identification of an early postmenopausal patient population that would benefit from preventive therapy.22,23

It is well recognized that it is never too late to initiate treatment to prevent fractures in postmenopausal women. Similarly, it is never too early in the postmenopause to evaluate women for bone loss and advise them on the steps to take to prevent the decline in bone mass and bone quality that increases their risk of future osteoporosis and fragility fractures.

Prevention of fragility fractures in secondary osteoporosis

Secondary osteoporosis represents an important area in the clinical management of bone mass loss, as several conditions are the cause of osteoporosis and fragility fractures (Table II). Treatment with glucocorticoid therapy is a common cause of osteoporosis and is associated with substantial morbidity. Although awareness of the condition has grown in recent years, it remains underdiagnosed and undertreated. Glucocorticoid induced osteoporosis is characterized by distinct features, such as acute bone loss and early fracture risk, emphasizing the importance of primary pharmacological intervention.24

Although a number of interventions for the management of glucocorticoid-induced osteoporosis have been evaluated, fracture reduction has not been a primary prevention end point in any study and data are only available as secondary end points or as safety data.25 Oral glucocorticoid use is one of the clinical risk factors included in the FRAX® algorithm, since its effect on fracture risk is partially independent of BMD.26 It is foreseeable that the estimation of fracture probability in glucocorticoid- treated individuals will be performed using FRAX®. Cancer-induced bone disease results from the primary disease, or from therapies against the primary condition causing secondary osteoporosis. Estrogen and androgen deprivation therapy in hormonal-responsive cancers, such as tumors of the breast and prostate, are recognized causes of reduced BMD and of increased fractures.27-30 These pharmacological complications are associated with an important morbidity and with a largely compromised quality of life. To preserve bone and reduce this morbidity, effective therapies,31,32 with a highly favorable risk-benefits ratio are available. However, in contrast to what happened for the recognition of glucocorticoid induced osteoporosis, reimbursement of the drugs used in primary pharmacological prevention is not universally recommended for antihormonal therapies.


Table II
Table II. Causes of secondary osteoporosis.

Abbreviations: LHRH, luteinizing hormone–releasing hormone; PPAR, peroxisome
proliferator–activated receptor.


Conclusions

The development of FRAX® promises to change the manner in which we target the treatment of osteoporosis from a BMD based approach to a fracture probability–based one. Using intervention thresholds based on absolute fracture probability means that age will not limit evaluation. The trend toward a risk-factor assessment approach to treating patients for osteoporosis is likely to draw attention to a cohort of subjects with normal or osteopenic BMD values. Further research into the efficacy of osteoporosis drugs for reducing the fracture risk in these patients is needed to determine more precisely the subset of patients in whom treatment will be most effective.

Acknowledgements. This work was supported through an unrestricted grant (to MLB) from F.I.R.M.O. Fondazione Raffaella Becagli.



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Keywords: antifracture agent; fragility fracture; osteoporosis; primary prevention