osteoporosis case study

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• Evidence-Based Guidelines
• Published: 14 March 2024

Evidence-Based Guideline for the management of osteoporosis in men

• Nicholas R. Fuggle   ORCID: orcid.org/0000-0001-5463-2255 1 ,
• Charlotte Beaudart 2 , 3 ,
• Olivier Bruyère 3 ,
• Bo Abrahamsen   ORCID: orcid.org/0000-0002-2730-6080 4 ,
• Nasser Al-Daghri 5 ,
• Nansa Burlet 3 , 6 ,
• Manju Chandran 7 ,
• Mario M. Rosa   ORCID: orcid.org/0000-0003-3158-2106 8 ,
• Bernard Cortet 9 ,
• Céline Demonceau 3 ,
• Willard Dere 10 ,
• Philippe Halbout 11 ,
• Mickaël Hiligsmann 12 ,
• John A. Kanis 13 , 14 ,
• Jean-Marc Kaufman 15 ,
• Andreas Kurth 16 ,
• Olivier Lamy 17 ,
• Andrea Laslop   ORCID: orcid.org/0009-0009-2707-3959 18 ,
• Stefania Maggi 19 ,
• Radmila Matijevic 20 ,
• Eugene McCloskey   ORCID: orcid.org/0000-0003-0177-8140 13 ,
• Ali Mobasheri   ORCID: orcid.org/0000-0001-6261-1286 21 ,
• Maria C. Prieto Yerro 22 ,
• Régis P. Radermecker 23 ,
• Shaun Sabico   ORCID: orcid.org/0000-0002-5248-2350 5 ,
• Yousef Al-Saleh 4 , 24 ,
• Stuart Silverman 25 ,
• Nicola Veronese   ORCID: orcid.org/0000-0002-9328-289X 26 ,
• René Rizzoli   ORCID: orcid.org/0000-0002-1537-422X 27 ,
• Cyrus Cooper   ORCID: orcid.org/0000-0003-3510-0709 1 , 28 , 29 ,
• Jean-Yves Reginster 3 , 30   na1 &
• Nicholas C. Harvey   ORCID: orcid.org/0000-0002-8194-2512 1 , 28   na1  

Nature Reviews Rheumatology volume  20 ,  pages 241–251 ( 2024 ) Cite this article

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• Osteoporosis
• Therapeutics

Historically, osteoporosis has been viewed as a disease of women, with research, trials of interventions and guidelines predominantly focused as such. It is apparent, however, that this condition causes a substantial health burden in men also, and that its assessment and management must ultimately be addressed across both sexes. In this article, an international multidisciplinary working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases presents GRADE-assessed recommendations for the diagnosis, monitoring and treatment of osteoporosis in men. The recommendations are based on a comprehensive review of the latest research related to diagnostic and screening approaches for osteoporosis and its associated high fracture risk in men, covering disease burden, appropriate interpretation of bone densitometry (including the use of a female reference database for densitometric diagnosis in men) and absolute fracture risk, thresholds for treatment, and interventions that can be used therapeutically and their health economic evaluation. Future work should specifically address the efficacy of anti-osteoporosis medications, including denosumab and bone-forming therapies.

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Introduction

Osteoporosis is a condition characterized by loss of bone mass and impaired bone microarchitecture that leads to a substantially increased risk of fracture. It is a highly prevalent, though often neglected, condition, which primarily affects women 1 . However, since the operational definition of osteoporosis was established in the 1990s 2 there has been relative uncertainty regarding the disease in men 3 , which has led to underdiagnosis of the condition and consequent undertreatment of this population 4 . This underdiagnosis persists, despite a backdrop of a considerable 5 , 6 and increasing 7 global burden of osteoporosis in men, which is associated with not only substantial morbidity but also excessive mortality compared with women with osteoporosis 8 .

It is estimated that in many populations one in five men over the age of 50 years will experience an osteoporotic fracture in their remaining lifetime 5 , 6 . As global populations age and expand, the number of fractures is expected to rise by 310% between 1990 and 2050 (ref.  7 ). The risk of hip fractures is greater in women than in men, but the gap lessens with increasing age 9 . In the Dubbo Osteoporosis Epidemiology Study the ratio of hip fracture incidence rates between men and women was 1:4.5 (95% CI 1.3–15.7) at age 60–69 years, 1:1.5 (95% CI 0.9–2.5) at age 70–79 years and 1:1.9 (95% CI 1.2–2.8) at age ≥80 years 10 . The prevalence of forearm fractures (using EU27 data from 2010) was approximately four times higher in women than in men (0.4% versus 0.1% of the population at risk) 11 , with a risk ratio of 4.5 between the sexes at the age of 50 years 5 .

Mortality rates also differ between the sexes, with men being at a substantially higher risk of death following a fracture than women, a difference thought to be attributable to excess comorbidity and infection rates 12 . In a group of older adults ≥60 years of age, inpatient mortality (median length of stay for survivors was 8 days with an interquartile range of 6–13 days) following a hip fracture was 10.2% in men compared with 4.7% in women, and 1-year mortality was 37.5% in men compared with 28.2% in women 13 . This elevated risk might persist for over 10 years 14 .

Age-related alterations to bone microarchitecture are differentially distributed across bone compartments in men and women. With increasing age, men experience trabecular bone loss driven largely by loss of trabecular thickness 15 , 16 but with connectivity intact, whereas women lose trabecular connectivity 17 , 18 . Skeletal ageing in men is also associated with reductions in cortical bone mineral density (BMD) with increasing, and encroaching, trabecularization of the cortex and periosteal apposition 19 .

Although the majority of guidelines pertaining to the management of osteoporosis focus on women, specific guidelines for osteoporosis in men do exist, such as the Endocrine Society 2012 clinical practice guideline 20 , 2021 French recommendations from the Groupe de Recherche et D’Information sur les Ostéoporoses (GRIO) in collaboration with La Société Française de Rheumatologie (SFR) 21 , and the Danish Endocrine Society–National Board of Health 2020 recommendations 22 . The Endocrine Society guideline recommends treatment for men ‘at high risk of fracture’, including (but not limited to) those with a history of fragility fracture of the hip or vertebra, men with a BMD 2.5 (or more) standard deviations below the mean value for normal young white men (using young white men as the reference population) or those in the USA with BMD within the osteopenic range and a 20% 10-year risk of major osteoporotic fracture or 10% risk of hip fracture 20 . SFR–GRIO recommends a ‘1,2,3 approach’ with an intervention threshold T-score <−1 for a man with a severe osteoporotic fracture and a T-score <−2 for a man with any fracture, and recommend treatment for any man if the T-score is <−3 (ref.  21 ). In terms of treatment choices, bisphosphonates are widely advocated 20 , 22 , with teriparatide recommended for men with multiple vertebral fractures and denosumab for men with prostate cancer 21 .

The management of osteoporosis in men is also included in general osteoporosis guidelines 23 , 24 , 25 , 26 but there is no clearly defined timetable for periodic revision of these recommendations and no consensus on the approach to management, leading to vast variation in the treatment of men with osteoporosis across the globe. This state of affairs clearly highlights the need for a new guideline informed by the latest developments in research and up-to-date expert opinion.

This Evidence-Based Guideline article documents the development and presentation of recommendations for the diagnosis, monitoring and treatment of osteoporosis in men, undertaken by an international working group.

In February 2023, the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) convened a working group to address the issue of ‘Osteoporosis in Men’. The working group included clinicians (rheumatologists, endocrinologists, orthopaedic surgeons), epidemiologists, public health and regulatory experts from at least 18 countries across three continents. At the meeting, the latest evidence regarding osteoporosis in men was reviewed and was synthesized with expert opinion to inform a GRADE (Grading of Recommendations Assessment, Development and Evaluation) 27 assessment of statements for the diagnosis, monitoring and treatment of osteoporosis in men. A session was held specifically for patient representation.

Literature search

Literature searches were performed (by B.A., C.B., O.B., N.R.F., N.C.H., M.H., J.A.K., J.M.K., J.Y.R. and R.R.) and the results were presented to the working group in a series of sessions, including sessions on screening and diagnosis, health economic aspects, patient perspectives (from patient representatives) and therapeutic interventions (a systematic review of the latter has been published 28 ). This evidence, together with expert opinion, was used to inform the GRADE assessment.

Grading of recommendations

After reviewing the evidence, the working group undertook a GRADE assessment to determine recommendations for the diagnosis, screening, treatment and monitoring of men with osteoporosis. For clarity, this GRADE assessment is not that used in the assessment of studies for meta-analysis, but has been modified for producing consensus around recommendations (and has been previously described 29 ).

The GRADE process involved expert members of the working group ( n  = 28) grading a list of statements (which had been formulated by the core writing group (J.Y.R., R.R., O.B., C.B., N.C.H. and N.R.F.) on the basis of a preliminary review of the evidence) (Supplementary Table  1 ) with a level of agreement (‘agree’ or ‘disagree’) and a strength of recommendation (‘recommended’ or ‘not recommended’, rated as ‘strong’ or ‘weak’ depending on the extent to which the member agreed with the statement) based on the considered quality of evidence, magnitude of effect, risk-to-benefit ratio, health economic data, values and preferences. Working group members were allowed to choose the most appropriate category and there was one round of voting. If members did not feel that the statement fell within their area of expertise it was graded ‘Not qualified’ and if a response was not provided the statement was graded ‘Not recorded’.

Statements addressed the appropriateness of using a reference database of women in the context of densitometric diagnosis of osteoporosis in men, using FRAX to assess fracture risk and in the setting of intervention thresholds (and whether these thresholds should be age-dependent), and the role of previous fracture in determining the decision to treat.

Treatment decisions were addressed in statements referring to the need for vitamin D and calcium repletion, first-line use of oral bisphosphonates, second-line use of zoledronate or denosumab and sequential therapy with bone-forming agents (or first-line use of these agents in accordance with regulatory authorities). The recommendation of physical activity and balanced diet was also covered.

Monitoring was addressed in statements regarding the use of bone turnover markers to monitor adherence and measurement of serum testosterone in pre-treatment assessment (together with the appropriateness of hormone replacement therapy).

Approaches to fracture risk assessment in men

Bmd and absolute fracture risk.

The original WHO consensus definition set the densitometric threshold for osteoporosis as an areal BMD of 2.5 standard deviations or more below the mean value for healthy young women, derived from the NHANES reference range 30 . This definitional approach has led to questions regarding whether the densitometric threshold for osteoporosis should be the same for men as for women 31 , 32 , 33 . Given that absolute BMD is on average higher in men than in women, it follows that using the same threshold and reference range in both sexes will lead to a lower prevalence of osteoporosis in men than in women. This approach seems appropriate, given the lower risk of fracture, on average, in men than in women. Furthermore, evidence suggests that the risk of hip fracture is very similar between sexes for a given absolute BMD, supporting the use of a common threshold and reference range 31 , 33 . Indeed, the gradient of risk (hazard ratio for fracture per unit decrease in BMD) is again very similar between men and women, and, in both sexes, the relative increase in fracture risk associated with a T-score of −2.5 declines with increasing age, because at older ages, a greater proportion of the population has a low T-score 34 . Finally, fracture risk varies substantially across the globe 35 , but BMD varies much less, suggesting that BMD contributes only part of the overall fracture risk. For example, the same T-score is associated with a different risk in Romania compared with that in Sweden 36 .

Thus, overall, the evidence supports the use of a common T-score threshold and the female NHANES reference range for both men and women. The question then arises of how best to incorporate BMD and other measures of risk into approaches to clinical risk assessment.

Although BMD is a reasonably specific marker of high fracture risk, it is not very sensitive. That is, people with a low BMD are individually at a high risk of fracture, but the majority of fractures happen in the population with a BMD above the T-score threshold of −2.5, simply because although they are at a lower risk of fracture individually, there are many more people in this population 34 . Thus, although BMD provides the definition of osteoporosis, it is only one of many risk factors for fracture. Improved capture of the risk associated with non-BMD risk factors enables improved risk prediction.

FRAX is a computer-based algorithm developed by the Sheffield WHO Collaborating Centre for Metabolic Bone Diseases and was first released in 2008 (ref.  37 ). The algorithm, intended for use in primary care, calculates fracture probability from easily obtainable clinical risk factors in men and women 38 . The output of FRAX is the 10-year probability of a major fracture (hip, clinical spine, humerus or wrist fracture) and the 10-year probability of hip fracture. Probability is calculated from the risk of fracture and death according to age, BMI and dichotomous risk factors comprising prior fragility fracture, parental history of hip fracture, current tobacco smoking, long-term use of oral glucocorticoids, rheumatoid arthritis, other causes of secondary osteoporosis and excessive alcohol consumption. Femoral neck BMD can be optionally inputted to enhance fracture-risk prediction 38 . The clinical risk factors considered in FRAX represent risk that is at least partly independent of BMD, and that, as with BMD, could be partly reversible with anti-osteoporosis treatment.

FRAX probability, which can be calculated with or without BMD (and potentially supplemented with trabecular bone score, which pertains to a measure of bone microarchitecture 39 , 40 ), thus presents a highly practicable metric with which to assess absolute fracture risk in an individual man or woman. However, the measure of risk by itself is of no use, unless it is linked to a decision regarding subsequent treatment with anti-osteoporosis medications. An intervention threshold is therefore required. Approaches to determining an intervention threshold are as much based on philosophy as on science, and necessarily encompass consideration of equity, health economics, willingness to pay, availability and cost of medicines, burden of disease and health care provision 34 . Broadly speaking, intervention thresholds have generally been based on BMD and/or fracture probability, with the presence of a prior fragility fracture in an older person generally being viewed as an indication for assessment and treatment. A detailed exposition of the merits and demerits of the different approaches has been recently reviewed (in 2023) and is beyond the scope of this article 34 . At the fundamental level, a fixed BMD T-score threshold of −2.5 is associated with a progressively lower effect on relative fracture risk with increasing age, as average population T-score declines with age and in the oldest decades may be lower than −2.5 (ref.  34 ), and is clearly hampered by the issues of poor sensitivity described above. A fixed fracture probability threshold risks undertreatment of younger individuals and overtreatment of older individuals. In European guidance on the management of osteoporosis in postmenopausal women issued by ESCEO and the International Osteoporosis Foundation (IOF) 41 , which is supported by other guidelines including the UK National Osteoporosis Guideline Group (NOGG) 23 , the intervention threshold at a particular age is set at the age-specific probability of a future major osteoporotic or hip fracture within the next 10 years, conveyed by the presence of a prior fragility fracture, without consideration of BMD, other clinical risk factors being absent, and BMI being average. This method leads to an intervention threshold that rises with age. Importantly, as life expectancy might be <10 years at older ages, and because FRAX probability integrates risk of fracture with risk of death, the metric represents the lifetime probability of fracture. For reasons of equity in relation to individuals who have experienced a prior fragility fracture, the UK NOGG guidance incorporates a hybrid intervention threshold, which rises with age until the age of 70 years and levels off thereafter. Given the marked variation in average fracture probability by country around the world, the age-dependent threshold approach, using specific country-calibrated FRAX models, ensures, together with health economic analyses, appropriateness for probability distributions in individual countries 34 .

The next question to arise is whether intervention thresholds should be the same in men and women. This approach has indeed been taken in the European (ESCEO–IOF) guidelines 41 , on the basis of equity (given that the metric represents absolute fracture risk), and that health economic analysis suggests that such an approach is similarly cost-effective in men and women.

Stratified targeting of anti-osteoporosis medications

Studies of both teriparatide and romosozumab have demonstrated greater and more rapid therapeutic effects with these anabolic agents than with oral antiresorptives 42 , 43 . Recognizing this development, and given the urgent need for therapeutic interventions in those at a very high risk of fracture, the ESCEO–IOF has recommended that individuals eligible for treatment be dichotomized into those at a ‘high risk’ and those at a ‘very high risk’ of fracture 44 , 45 . In this way, patients at a very high risk of fracture can be directed to the more expensive, but more efficacious, anabolic therapy first 42 , 43 , 46 , 47 , whereas those at a ‘high risk’ can be directed to an antiresorptive agent such as a bisphosphonate or denosumab 45 .

Consistent with the age-dependent approach to the intervention threshold, in the ESCEO–IOF approach a ‘very high risk’ can be defined as a fracture probability that lies above the upper assessment threshold (1.2 times the intervention threshold) after a FRAX assessment, with or without the inclusion of BMD (if BMD testing is unavailable) 44 , 48 . A similar, but hybrid, approach has been applied nationally in the UK NOGG recommendations 49 , in which the threshold is adapted to incorporate the constant probability threshold above the age of 70 years 50 . The next question to address is what attributes and clinical risk factors are associated with FRAX probabilities in the ‘low’, ‘high’ and ‘very high’ fracture risk categories. In this setting, it is apparent that the presence of a single clinical risk factor rarely leads to a categorization of very high fracture risk, but a combination of risk factors, particularly older age, recent fracture and glucocorticoid use 49 .

There are several routes to an individual being categorized as being at a very high risk of fracture on the basis of their FRAX probability score. A key contributor is prior fragility fracture. Thus, studies have demonstrated that fracture risk is acutely elevated immediately after an index fracture and that this risk wanes over the following 2 years but does not return to baseline and subsequently increases with age 51 , 52 , 53 , 54 . Although a fracture at any time in the past is associated with an increased risk of an incident fracture, when this prior fragility fracture has occurred within the past 24 months the excess risk is even greater 55 , 56 . This pattern has been most comprehensively assessed in the Iceland Reykjavík cohort 51 , 56 , and further data from the Reykjavik Study have shown that, in individuals who sustained a recurrent fracture, 31–45% of these fractures occurred within 1 year of the first (sentinel) fracture, depending on the fracture site 56 . Importantly, the transient increase in risk following an index fracture is of sufficient magnitude to materially alter the subsequent 10-year probability of fracture 56 . Multipliers specific to age, sex and fracture site have been generated to modify FRAX probability, enabling the physician to accommodate the excess risk associated with recency and particular fracture types 57 . A platform enabling the easy incorporation of the multiplier as a modifier of the FRAX calculator has been developed and is available online as FRAXplus 58 . A key advantage of this approach is that recency and site of fracture, along with other modifiers of FRAX probability, for example, dose of glucocorticoids or trabecular bone score 59 , can be used to modify FRAX probability in a way that is immediately interpretable in the context of current national guidelines that are based on 10-year FRAX probability 45 .

Biochemical assessment

Biochemical assessments in men with osteoporosis can be helpful in diagnosis and also in fracture risk assessment, providing information complementary to that from FRAX and BMD. In addition to renal function, bone profile (including phosphate) and screening for secondary causes of osteoporosis, bone turnover markers and serum (free) testosterone can also assist in the management of men with osteoporosis 48 .

Bone turnover markers, including procollagen type I N-propeptide (P1NP) and C-terminal telopeptide (CTX) can be measured prior to treatment and again at 3 months to ascertain whether the suppression of bone turnover has been adequately achieved and medication adherence has been satisfactory 48 , 60 .

Increased levels of bone turnover markers have been shown to be associated with a greater extent of bone loss and periosteal expansion in men 61 , thus justifying their inclusion in the algorithm of clinical treatment for osteoporosis in both men and women 48 .

Serum total testosterone concentration, complemented by free testosterone concentration if serum values are borderline and/or in a clinical situation in which testosterone binding might be altered (for example, by obesity or glucocorticoid use), can also be measured to identify those men who are hypogonadal and who might therefore benefit from testosterone supplementation 62 , 63 .

Therapeutic interventions for men with osteoporosis

Many studies of anti-osteoporosis medications have been performed in post-menopausal women; however, some trials have specifically sought to address the issue of efficacy and safety of these agents in the male population. One issue is that the majority of these studies are limited in their ability to address fracture incidence as an outcome and so regulatory authorities have sanctioned the use of ‘bridging’ studies 64 that look at the similarity of BMD response between men and women with a similar fracture risk. In this case, the primary outcome is improvement in BMD rather than fracture risk, and thresholds for benefit (surrogate threshold effect) have been proposed 65 with differences between the change in BMD in the intervention group versus the placebo group of 1.83% for any fracture, 1.42% for vertebral fracture, 3.18% for hip fracture and 2.13% for non-vertebral fracture 65 , 66 (Fig.  1 ). These thresholds are derived from a large series of trials in women with changes in fracture risk in relation to changes in total hip BMD. We can therefore use this approach when examining historical trials of therapeutic interventions for osteoporosis in men 28 .

The figure provides a representation of the percentage improvement of total hip bone mineral density (BMD) with use of anti-osteoporosis medications including alendronate, risedronate, zoledronate, ibandronate, denosumab, abaloparatide and romosozumab 28 . Thresholds for benefit (surrogate threshold effect (STE)) 65 , 66 for fracture, depicted as horizontal lines on the graph, are 3.18% for hip fracture, 2.13% for non-vertebral fracture, 1.83% for all fractures and 1.42% for vertebral fractures. These thresholds are derived from a large series of placebo-controlled trials evaluating various anti-osteoporosis agents in women with osteoporosis.

Antiresorptive agents (bisphosphonates and denosumab)

A rich body of literature supports the use of oral bisphosphonates for osteoporosis in men, with studies ranging in duration from 6 months 67 to 3 years 68 having demonstrated significant improvements in femoral neck BMD. These benefits were documented in a 2023 systematic review and meta-analysis: alendronate monotherapy improved BMD at the lumbar spine with a mean difference (MD) of 5.2% (95% CI 2.76–7.64), total hip with an MD of 2.34% (95% CI 1.66–3.03) and femoral neck with an MD of 2.53% (95% CI 1.76–3.31), and risedronate monotherapy improved BMD at the lumbar spine with an MD of 4.39% (95% CI 3.46–5.31), total hip with an MD of 2.46% (95% CI 1.71–3.22) and femoral neck with an MD of 1.95% (95% CI 0.62–3.27) 28 . Two studies of zoledronate 69 , 70 reported significant improvements in lumbar spine BMD (MD 6.10%; 95% CI 4.99–7.21) 70 , femoral neck BMD (MD 3.1%; 95% CI 2.2–5.4) and total hip BMD (MD 3.8%; 95% CI 2.2–5.4). Benefits for vertebral fracture incidence were also observed following 12 months of zoledronate treatment and 24 months of follow-up in one of the studies (relative risk 0.33; 95% CI 0.16–0.7, P   =  0.002) 70 , but no benefits for fracture outcomes were observed in the other study 69 . A head-to-head comparison of zoledronate and alendronate found that zoledronate was not inferior to alendronate, but did not demonstrate the superiority of zoledronate 71 . One study investigated the efficacy of ibandronate in 132 men and reported significant improvements in lumbar spine BMD (MD 2.58%; 95% CI 1.41–3.76) and total hip BMD (MD 2.13%; 95%CI 1.34–2.92) at 1 year 72 . Denosumab administered via 6-monthly subcutaneous injections seemed to provide benefits in BMD accrual compared with placebo in randomized controlled trials of 242 men 73 and 47 men 74 with osteoporosis over 2 years of follow-up. The results of a 2023 meta-analysis demonstrated the benefits of denosumab for BMD at the lumbar spine with an MD of 5.80% (95% CI 3.5–8.1), femoral neck BMD with an MD of 2.07% (95% CI 1.23–2.92) and total hip BMD with an MD of 2.28% (95% CI 1.51–3.04) 28 .

Thus, the evidence base strongly supports the use of bisphosphonates or denosumab in the treatment of osteoporosis in men, and suggests that oral bisphosphonates should be recommended as first-line therapy with intravenous bisphosphonates as second-line therapy (similar to the approach taken for the treatment of post-menopausal women 41 ).

Adherence is a substantial issue when considering any therapy 75 but particularly so with oral bisphosphonates (owing to complexities of dosing regimes and adverse effects) 76 , 77 , 78 . Adherence can be monitored by measurement of bone turnover markers at baseline and at 3 months to identify a decrease above the least significant change (that is, reductions of more than 38% for P1NP and 56% for CTX), an approach that is supported by international guidelines 60 .

Anabolic agents

Teriparatide has been compared with placebo in two studies, one with 309 men with osteoporosis followed over 11 months 79 and the other involving 23 men for 18 months 80 . Meta-analysis of these studies showed that teriparatide treatment significantly improved BMD at the lumbar spine (MD 8.19%; 95% CI 1.14–15.25) and femoral neck (MD 1.33; 95% CI 0.39–2.27) 28 . Teriparatide has been compared with alendronate in two head-to-head studies, in which teriparatide treatment led to significantly greater increases in BMD at the lumbar spine 81 , 82 and femoral neck 82 . Comparisons with risedronate indicated a lack of superiority of teriparatide unless teriparatide was followed by risedronate 83 , supporting the drive towards sequential therapy when bone-forming agents are employed. Two studies published in 2022 investigated the effect of abaloparatide versus placebo in a total of 248 men with osteoporosis over a period of 12 months in a trial in the USA, Poland and Italy 84 and over 18 months in a Japanese population 85 . Meta-analysis of the two studies demonstrated a significant improvement in abaloparatide-treated patients in BMD at the lumbar spine (MD 11.29%; 95% CI 1.80–20.8), femoral neck (MD 3.98%; 95% CI 1.10–6.85), and total hip (MD 3.91%; 95% CI 0.34–7.49) 28 . Only one study has compared romosozumab with placebo, in 245 men over a 12-month period. This study found significantly greater improvements in the romosozumab group than in the placebo group ( P   <  0.001 for all comparisons) in percentage change in BMD at the lumbar spine (12.1% versus 1.2%), femoral neck (2.2% versus −0.2%) and total hip (2.5% versus −0.5%) 86 . The possibly increased risk of cardiovascular adverse events should be considered when using romosozumab in men 87 .

Hormone replacement therapy

Reductions in sex steroid production and increases in levels of sex hormone binding globulin (SHBG) reduce the availability of free testosterone in men as they age 63 , 88 .Testosterone is released from the testes in response to luteinizing hormone stimulation and is converted to oestradiol via aromatase (CYP19A1). Oestradiol is thought to mediate the major downstream effects on bone homeostasis as it acts on osteoclasts, osteoblasts and osteocytes via binding to α and β oestrogen receptors. Indeed, oestradiol was shown to mediate the main effects of testosterone on bone homeostasis in healthy men 20–50 years of age treated with a gonadotropin hormone-releasing hormone (GnRH) analogue to suppress endogenous testosterone and receiving testosterone replacement with or without an aromatase inhibitor 89 , 90 , 91 . Profound hypogonadism, such as in androgen deprivation therapy for prostate cancer, is a well known cause of osteoporosis and increased fracture risk. As for endogenous sex steroid levels in community-dwelling older men, most data suggest a role of low oestradiol levels in increased bone loss and fracture risk and, with some exceptions 90 , no clear association of testosterone levels with bone loss and fracture incidence 91 .

One of the important initiatives in understanding the role of testosterone replacement in men was the series of ‘T-trials’ emanating from the National Institute on Aging. The T-trial specifically for bone demonstrated a significant increase (7%) in lumbar spine trabecular volumetric BMD after 1 year of testosterone replacement 92 . Bone microarchitectural benefits were also observed after 2 years of testosterone replacement (compared with placebo), with significant increases in cortical volumetric BMD (3%) and significant increases in areal BMD at the lumbar spine and hip 93 .

However, consistently robust benefits of testosterone replacement therapy have not been demonstrated. In a systematic review and meta-analysis of testosterone therapy, benefit was only observed in lumbar spine BMD and only in a hypogonadal population 62 .

Answers might come from the TRAVERSE (Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men) trial of testosterone supplementation versus placebo (in men with hypogonadal symptoms, low serum testosterone levels and high cardiovascular risk), which demonstrated cardiovascular safety of supplementation as the primary end point; the  supplementary material in this paper states that clinical fracture outcomes will be discussed in a future publication 94 .

The potential for hormone replacement therapy to benefit BMD in hypogonadal men supports the assessment of serum total or free testosterone levels in men undergoing investigation for osteoporosis, and in those with established osteoporosis. However, there is a lack of controlled data on fracture incidence in response to testosterone therapy, and owing to the specificity of this treatment for men, it is not possible to ‘bridge’ from the effects on fracture in studies in women.

For the above reasons, serum free or total testosterone levels should be measured as a facet of the investigatory ‘work-up’ for osteoporosis in men. Testosterone therapy might be indicated in the case of symptomatic deficiency, with the decision to recommend testosterone therapy made on the basis of a holistic assessment of the patient across bone, cardiometabolic and sexual function, ideally in conjunction with endocrinology expertise. Furthermore, hypogonadal men with osteoporosis should usually be treated with an established anti-osteoporosis medication, regardless of whether testosterone therapy is instituted, in order to most effectively reduce fracture risk.

Efficacy summary

From the studies reported above, it is clear that anti-osteoporosis medications can substantially benefit the male skeleton in the case of osteoporosis via the accrual of BMD, but also via demonstrated improvements in fracture outcomes 70 . First-line treatment with oral bisphosphonates followed by second-line deployment of intravenous bisphosphonates and denosumab is supported as an approach to anti-resorptive therapy (driven by the relative ease and cost of administration of these oral agents, compared with health care professional-delivered intravenous and subcutaneous preparations). For those men who would benefit from initial bone-forming therapy, the available data on BMD supports the utility of abaloparatide (Fig.  1 ), although further studies and collection of data on teriparatide should be a research priority.

Health economic aspects

In addition to their substantial effects on morbidity and mortality, there are considerable costs associated with osteoporosis and fragility fractures in men. For payers and policy-makers to develop a robust strategy to combat osteoporosis in men, they require evidence not only of clinical efficacy but also of economic value. This need is set within a competitive landscape of rising demands for health care but limited resources, and so the case for resource and funding for osteoporosis in men needs to be made.

Studies in the USA have shown that men account for a quarter of the overall cost of fractures 95 and a claims database study found that the average cost of a fracture is notably greater in men than in women ($52,000 versus $17,000) 96 . The authors hypothesized that the reason for this discrepancy could be the fact that fractures in men are associated with greater co-morbidity.

The cost-effectiveness of osteoporosis interventions in men was investigated in a 2023 systematic review of relevant studies, including those concerning anti-osteoporosis medications (8 studies), nutritional interventions (4 studies), screening strategies (6 studies), intervention thresholds (5 studies) and post-fracture care programmes (2 studies) 97 . The systematic review found that there were fewer studies in men than in women and that those that were published were largely from the USA or Europe and only two had been published in the preceding 5 years, highlighting the need for up-to-date research in this area 97 . The quality of the studies was fair, with a score of 18.8 out of 25 (range 13–23.5) 97 . This systematic review also examined the breadth of input data used in economic models and, interestingly, found that although there was men-specific data for hip fracture incidence, hip fracture cost, baseline mortality and excess mortality, the vast majority of inputs (for example, ‘treatment effects’) used combined or even women-only inputs for economic modelling, potentially introducing inaccuracy into the model and, again, highlighting the need for more high-quality research into osteoporosis in men.

In terms of the cost-effectiveness of medications, oral bisphosphonates have been proven cost-effective in men 55 years of age or older with a history of fracture, low bone mass, rheumatoid arthritis or use of high-dose glucocorticoids 98 , 99 , 100 , 101 , 102 , although there are no studies comparing the cost-effectiveness of different bisphosphonate formulations. Denosumab was shown to be cost-effective in comparison with bisphosphonates and teriparatide in high-risk populations 103 , 104 , and calcium and vitamin D supplementation (or vitamin D-fortified dairy products) were cost-effective in all men >80 years of age and in men >60 years of age with osteoporosis 105 , 106 , 107 . With regard to medications for men with osteoporosis, there are important gaps in the literature that need to be closed, for example, demonstration of the cost-effectiveness of denosumab for treating glucocorticoid-induced osteoporosis.

Screening for osteoporosis, using BMD as measured by dual-energy X-ray absorptiometry (DXA), was cost-effective in a cohort of men who had sustained a fall 108 and a study in US men suggested that a fracture risk assessment strategy using age, femoral neck BMD and vertebral fracture assessment (with DXA) would be cost-effective for men 50–60 years of age 109 . However, in Switzerland, a DXA-based population screening approach (followed by treatment with alendronate for cases of osteopenia with fracture or defined osteoporosis) was not found to be cost-effective in men (although it was in women) 110 , reflecting geographic variation in factors that influence cost-effectiveness, as well as in the screening approaches taken.

Post-fracture care services (centred on secondary fracture prevention and models including fracture liaison services or orthogeriatric services) were universally cost-effective in Sweden (with zero net costs and 35 quality-adjusted life years gained compared with a ‘do nothing’ approach) 111 and in the UK (at £14,525 per quality-adjusted life years for orthogeriatric services aimed at men 83 years of age) 112 .

The aforementioned systematic review found no significant difference in the cost-effectiveness of intervention thresholds between men and women 97 . However, when dissecting studies that included men and women, the incremental cost-effectiveness ratio (calculated as the difference in the cost of an intervention divided by the difference in the effect of an intervention) was numerically superior for men than for women in 75% of the studies examined and was inferior for men in 25% of those studies 97 . It should be noted that 73% of studies concluded that, although numerically different, there was no statistically significant difference in cost-effectiveness between men and women 97 .

An important consideration is the use of sequential therapies (that is, the use of a bone-forming agent followed by an anti-resorptive agent), and in this area a regimen of abaloparatide followed by alendronate was dominant over alendronate monotherapy or biosimilar teriparatide followed by alendronate in a cohort of US men with a BMD T-score ≤−2.5 and a history of fracture 113 , in terms of cost-effectiveness. This finding, however, remains to be demonstrated in other populations.

As well as the direct costs of fracture care and prevention, there are also the notable consequences of impacts on social care, increased mortality and the increased risk of subsequent fractures.

In summary, osteoporosis in men gives rise to a substantial health economic burden. Cost-effective interventions for osteoporosis in men exist, including medications, screening approaches, post-fracture care and sequential therapy, and, overall, the cost-effectiveness of these interventions is similar between men and women. However, further research focused on male populations is required to close knowledge gaps concerning epidemiology, costs and model inputs, in order to tailor health economic outputs in this population. These health economic factors were considered by the working group when grading recommendations.

Physical exercise and a balanced diet

The skeletal benefits of physical activity, a balanced diet and calcium and vitamin D supplementation have been well-documented.

Aside from cardiometabolic benefits, evidence supports the skeletal benefits of exercise, including weight-bearing exercise, resistance exercise and multi-modal approaches 114 . This literature is further fortified by a 2021 trial, focused on men, which demonstrated that a multi-component exercise approach had significant benefits for BMD in middle-aged and older men 115 . Although the benefits of exercise interventions have not demonstrated a reduction in fracture (as an end point) in a public health realm 116 , on the basis of BMD associations and adjunctive benefits across organ systems, it is usually appropriate to recommend exercise to men with osteoporosis.

A 2020 systematic review that served as an update of a 2019 Cochrane review of evidence for the effect of exercise on prevention of falls found that exercise reduces the risk of falls by 23% (ref.  117 ), again emphasizing the potential benefits of exercise on musculoskeletal health. The effect of falls on fracture risk has also been included in FRAXplus 58 , with the option to adjust the 10-year fracture probability according to the number of falls occurring in the past year (0, 1, 2 and 3 or more falls).

Balanced diet and supplementation

Advocating a balanced diet is recommended for men with osteoporosis, echoing similar guidelines in women 41 . Adequate protein intake is important and consumption at levels that are higher than the recommended daily allowance might be of benefit to skeletal health 118 , 119 .

The above should be considered in light of particular diets, with vegetarian and vegan diets seeming to potentially reduce BMD 120 and caloric restriction (although not intermittent fasting) being associated with lower BMD 120 .

In general, 800–1200 mg of calcium should be consumed via the diet on a daily basis; calcium supplementation can be considered if the daily intake is below 800 mg and vitamin D supplementation (800 IU) should be considered for those at an increased risk of fracture and those in whom vitamin D levels are insufficient 41 .

Patient perspectives of osteoporosis in men

Patient preference and perspectives are important to consider in the development of recommendations, to ensure that a patient-centred approach is adopted 121 . In the development of the recommendations presented herein, the working group included patient input, which highlighted patients’ expectations of a clinical approach to osteoporosis.

With regard to the treatment of osteoporosis in men, it was emphasized by the patient representation that anti-osteoporosis therapy was desired as quickly as possible as patients want to ‘stop the clock of bone metabolism’ in order to ‘have no further fractures’.

In our qualitative work examining patient preferences, no concern was forthcoming from the patients that osteoporosis was considered a ‘female’ condition and so associated with a stigma. However, a review of wider experience (that is, beyond the working group) suggests that clinicians should consider this potential issue when managing men with osteoporosis. For example, a 72-year-old patient in another study was quoted as saying “When I was first diagnosed my first thought was ‘why have I got it, isn’t this just for old women?’” 122 .

Also, no issues with adherence were reported to the working group, although previous estimates have suggested that up to 64% of men are non-adherent to bisphosphonate therapy by 12 months 123 , highlighting the need for patient education, counselling and, potentially, adherence monitoring 78 .

Summary of recommendations and guidelines

Here we summarize the recommendations of the working group for the diagnosis, screening, assessment and treatment of men with osteoporosis. The statements supported by the working group are itemised below and detailed ratings are presented in Supplementary Table  1 . Statements were graded ‘weak recommendations’ if 75% of voters selected either ‘strong do’ or ‘weak do’, and were graded as ‘strong recommendations’ if 75% of voters selected ‘strong do’.

A female reference database should be used for the densitometric diagnosis of osteoporosis in men (strong recommendation).

FRAX is the appropriate tool for the assessment of fracture risk and as the basis for setting intervention thresholds in men with osteoporosis (strong recommendation).

FRAX-based intervention thresholds should be age dependent in men with osteoporosis (strong recommendation).

Trabecular bone score, used with BMD and FRAX probability, provides useful information for fracture risk assessment in men (weak recommendation).

All men with a prior fragility fracture should be considered for treatment with anti-osteoporosis medications (strong recommendation).

The anti-osteoporosis treatment regimen in men should be adapted to an individual’s baseline fracture risk (strong recommendation).

Vitamin D and calcium repletion should be ensured in all men above the age of 65 years (strong recommendation).

Oral bisphosphonates (alendronate or risedronate) are first-line treatments for men at a high risk of fracture (strong recommendation).

Denosumab or zoledronate are second-line treatments for men at a high risk of fracture (strong recommendation).

A sequential therapy starting with a bone-forming agent followed by an anti-resorptive agent should be considered for men at a very high risk of fracture (strong recommendation).

Biochemical markers of bone turnover are the appropriate tool to assess adherence to anti-resorptive therapy in men (weak recommendation).

Bone-forming agents, when given as first-line treatment in men at a very high risk of fracture, should be used in accordance with the recommendations of the regulatory authorities (strong recommendation).

Physical exercise and a balanced diet should be recommended to all men with osteoporosis (strong recommendation).

Serum total testosterone should be assessed, as part of the pre-treatment assessment of men with osteoporosis (weak recommendation).

Appropriate hormone replacement therapy should be considered in men with low levels of total or free serum testosterone (weak recommendation).

Based on available BMD data, abaloparatide is considered an appropriate first-line treatment for men with osteoporosis at a very high risk of osteoporotic fracture (weak recommendation).

It should be noted that these recommendations should be taken as a whole, and not in isolation. For example, the recommendation “All men with a prior fragility fracture should be considered for treatment with anti-osteoporosis medications” should be interpreted in the context of those recommendations recommending the assessment of fracture risk using FRAX.

In addition, given that prior fracture is such a strong predictor of future fracture, and in line with other national 23 and international 41 guidelines, treatment should be strongly considered in those who have sustained a fracture. In the UK NOGG guideline, it is suggested that FRAX can be used to adjudicate the type of anti-osteoporosis treatment used in those with a prior fragility fracture 23 , and in European guidelines, it is recommended that all women over 65 years of age be considered for treatment if they have sustained a prior fracture, without the need for further assessment 41 .

Unlike previous guidelines 20 , 21 , 22 , these recommendations address the particular issue of the sex of the reference population used in the densitometric diagnosis of osteoporosis in men, provide guidance for the usage of FRAX in this population and delineate the use of pharmacological approaches for the treatment of osteoporosis in men based on the latest, systematically evaluated evidence 28 . This review provides a particularly timely perspective, as anabolic therapies become increasingly available in clinical practice.

Limitations and research outlook

Although the method of producing the above guidelines is robust, the recommendations are constrained by the current limitations in terms of the scope of research regarding osteoporosis in men. Future research should be particularly aimed at addressing treatment efficacy, focusing on denosumab, abaloparatide, teriparatide and romosozumab, and further studies are required to determine the role of testosterone in the treatment of osteoporosis in men.

Conclusions

In conclusion, osteoporosis in men continues to be a substantial clinical and health economic concern for health care workers, policy-makers and, most importantly, patients. Medications for reducing fracture risk exist and evidence of their efficacy is presented above, as are robust recommendations to enable clinicians to navigate this potentially difficult area of clinical practice. In terms of treatment, these guidelines advocate the use of oral anti-resorptive agents as first-line agents in men at a high risk of fracture and the use of bone-forming agents followed sequentially by anti-resorptive agents in men at a very high risk of fracture (with abaloparatide supported by the strongest data with respect to BMD changes), following an approach similar to that advocated for women with osteoporosis 41 .

We finish by emphasizing that osteoporosis in men is an area of relative neglect, and that further research, investment and focus is required to address some fundamental areas of the disease in this patient group.

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Acknowledgements

The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group that produced this Evidence-Based Guideline was funded by the ESCEO. The ESCEO receives unrestricted educational grants to support its educational and scientific activities from non-governmental organisations, not-for-profit organisations, non-commercial or corporate partners. The choice of topics, participants, content and agenda of the working group as well as the writing, editing, submission and reviewing of the manuscript are the sole responsibility of the ESCEO, without any influence from third parties. The authors wish to thank and acknowledge their patient partners who provided expert patient input and insight.

Author information

These authors jointly supervised this work: Jean-Yves Reginster, Nicholas C. Harvey.

Authors and Affiliations

MRC Lifecourse Epidemiology Centre, University of Southampton, Southampton, UK

Nicholas R. Fuggle, Cyrus Cooper & Nicholas C. Harvey

Clinical Pharmacology and Toxicology Research Unit, Faculty of Medicine, NARILIS, University of Namur, Namur, Belgium

Charlotte Beaudart

WHO Collaborating Centre for Epidemiology of Musculoskeletal Health and Ageing, Liège, Belgium

Charlotte Beaudart, Olivier Bruyère, Nansa Burlet, Céline Demonceau & Jean-Yves Reginster

Odense Patient Data Explorative Network, Institute of Clinical Research University of Southern Denmark, Odense, Denmark

Bo Abrahamsen & Yousef Al-Saleh

Chair for Biomarkers of Chronic Diseases, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia

Nasser Al-Daghri & Shaun Sabico

The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), Liege, Belgium

Nansa Burlet

Osteoporosis and Bone Metabolism Unit, Department of Endocrinology, Singapore General Hospital, DUKE NUS Medical School, Singapore, Singapore

Manju Chandran

Laboratory of Clinical and Therapeutical Pharmacology, University of Lisbon, Lisbon, Portugal

Mario M. Rosa

Department of Rheumatology, University of Lille, Lille, France

Bernard Cortet

Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA

Willard Dere

The International Osteoporosis Foundation (IOF), Nyon, Switzerland

Philippe Halbout

Department of Health Services Research, CAPHRI Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands

Mickaël Hiligsmann

Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK

John A. Kanis & Eugene McCloskey

Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia

John A. Kanis

Department of Endocrinology, Ghent University Hospital, Ghent, Belgium

Jean-Marc Kaufman

Department of Orthopaedic and Trauma Surgery, Community Clinics Middle Rhine, Campus Kemperhof, Koblenz, Germany

Andreas Kurth

Centre interdisciplinaire des maladies osseuses, Département de l’appareil locomoteur, Centre hospitalier universitaire vaudois, Lausanne, Switzerland

Olivier Lamy

Scientific Office, Federal Office for Safety in Health Care, Vienna, Austria

Andrea Laslop

CNR Aging Branch-IN, Padua, Italy

Stefania Maggi

University of Novi Sad, Faculty of Medicine, Clinic for Orthopedic Surgery and Traumatology, Clinical Center of Vojvodina, Novi Sad, Serbia

Radmila Matijevic

Research Unit of Medical Imaging, Physics, and Technology, Faculty of Medicine, University of Oulu, Oulu, Finland

Ali Mobasheri

Agencia Española de Medicamentos y Productos Sanitarios, Madrid, Spain

Maria C. Prieto Yerro

Department of Diabetes, Nutrition and Metabolic disorders, Clinical pharmacology, University of Liège, CHU de Liège, Liège, Belgium

Régis P. Radermecker

Department of Endocrinology, Dr. Mohammad Alfagih Hospital, Riyadh, Saudi Arabia

Yousef Al-Saleh

Department of Medicine, Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Stuart Silverman

Department of Internal Medicine, Geriatrics Section, University of Palermo, Palermo, Italy

Nicola Veronese

Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland

René Rizzoli

NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK

Cyrus Cooper & Nicholas C. Harvey

NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK

Cyrus Cooper

Protein Research Chair, Biochemistry Department, College of Science, King Saud University, Riyadh, Kingdom of Saudi Arabia

Jean-Yves Reginster

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Contributions

N.R.F., C.B., O.B., B.A., M.H., J.A.K., J.M.K., R.R., C.C., J.Y.R. and N.H. researched data for the article. N.R.F., C.B., O.B., B.A., N.B., M.C., M.R.R., B.C., W.D., P.H., M.H., J.A.K., J.M.K., A.K., O.L., A.L., S.M., R.M., E.M., A.M., M.C.P.Y, R.P.R., S.Si., N.V., R.R., C.C., J.Y.R. and N.H. contributed substantially to discussion of the content. N.R.F., C.B., O.B., M.C., M.R.R., B.C., W.D., M.H., J.A.K., J.M.K., O.L., S.Si., R.R., J.Y.R. and N.H. wrote the article; N.R.F. and C.B. are joint first authors. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Nicholas C. Harvey .

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Competing interests.

N.R.F. declares that he has received travel bursaries from Eli Lilly and Pfizer and speaker’s fees from Viatris outside the submitted work. B.A. declares that he has received speaker and/or consulting fees from UCB, Amgen, Kyowa-Kirin, and Pharmacosmos, and institutional research grants (with funds paid to the institution) from Novartis, Kyowa-Kirin and Pharmacosmos; he is a member of the Executive Committee of the European Calcified Tissue Society. O.B. declares that he has received consulting or lecture fees from Amgen, Aptissen, Biophytis, IBSA, Mylan, Novartis, Orifarm, Sanofi, UCB and Viatris outside the submitted work. B.C. declares that he has received personal fees, consultancy, lecture fees and/or honoraria from Alexion, Amgen, Expansience, Kyowa-Kirin, MSD, Novartis,Theramex, UCB, Viatris. M.C. declares that she has received honoraria from Kyowa Kirin and AMGEN for speaking and chairing engagements. W.D. declares that he is a shareholder and former employee of Amgen, and former board of director member of Radius Health. M.H. declares that he has received research grants (paid to his institution) from Radius Health and Amgen, consulting fees from UCB and lecture fees from Mylan Pharmaceuticals and IBSA (paid to his institution), outside this work. J.A.K. declares that he is a director of Osteoporosis Research Ltd, a member of the National Osteoporosis Guideline Group (UK), a member of the International Osteoporosis Foundation, and a member of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO). J.M.K. declares that he is a board member (treasurer) of ESCEO. S.M. declares that she has received research grants and personal fees as an advisory board member and/or speaker fees from GSK, Pfizer, Merck, Sanofi, Takeda, Novavax, Viatris and Janssen outside the submitted work. R.M. declares that she has received personal fees from Amicus, ElPharma, Abela Pharm. A.K. declares that he has participated in advisory boards for Amgen, UCB, Agnovos, Alexion, Image Biopsy Lab, Theramex and speakers bureau for Amgen, Merit Medical, UCB, Agnovos, Alexion, Theramex, Stada; he is president of the Dachverband Osteologie e.V., Germany. M.M.R. declares that he is a Member of the Scientific Advice Working Party and Member of the Central Nervous System Working Party at the European Medicines Agency. S.Si. declares that he has received grant support from Amgen, consultancy fees from Amgen and Radius. N.V. declares that she has received personal fees from IBSA, Mylan, Viatris, Fidia, MSD, Bayer outside this work. R.R. declares that he has received fees as a speaker or consultant for Abiogen, Effryx, Nestlé, ObsEva and Theramex. C.C. declares that he has received personal fees from ABBH, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier and Takeda. J.Y.R. declares that he has received consulting fees or been on paid advisory boards for IBSA-Genevrier, Mylan, Radius Health, Pierre Fabre, Faes Pharma, Rejuvenate Biomed, Samumed, Teva, Theramex, Pfizer, Mithra Pharmaceuticals, received lecture fees when speaking at the invitation of the sponsor for IBSA-Genevrier, Mylan, Cniel, Dairy Research Council (DRC), Nutricia, Danone, Agnovos and received grant support from IBSA-Genevrier, Mylan, Cniel, Radius Health, TRB. N.C.H. declares that he has received personal fees, consultancy, lecture fees and/or honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, UCB, Kyowa Kirin, Servier, Shire, Consilient Healthcare, Theramex and Internis Pharma. The other authors declare no competing interests.

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Fuggle, N.R., Beaudart, C., Bruyère, O. et al. Evidence-Based Guideline for the management of osteoporosis in men. Nat Rev Rheumatol 20 , 241–251 (2024). https://doi.org/10.1038/s41584-024-01094-9

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DOI : https://doi.org/10.1038/s41584-024-01094-9

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Osteoporosis

Marissa, Jeremy, and Eleanor

By Lisa Marie Rubin

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This directed case study focuses on the physiology of bone homeostasis and methods of prevention and treatment of osteoporosis. One of the overall purposes of the case is to show students that osteoporosis is not simply a disease that afflicts elderly women. Instead, students learn about Marissa, a petite 15-year-old who has just learned that her 55-year-old grandmother has osteoporosis; Jeremey, a lanky 19-year-old college sophomore who recently has become interested in weight-lifting and is thinking about using steroids to bulk up; and Eleanor, a 45-year-old woman considering hormone replacement therapy mainly to prevent osteoporosis. The case is appropriate for use in an introductory nutrition course, physiology course, pathophysiology course, or general education course focusing on the human body and disease.

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• Define osteoporosis and list risk factors for it.
• Describe the roles of osteoblasts and osteoclasts in bones.
• Understand basic bone physiology and the concept of peak bone mass.
• Explain how hormones (specfically, PTH, calcitonin, and estrogen) affect bone and blood calcium levels.
• Understand that bones serve as calcium reservoirs.
• Explain why calcium is vital to bone health.
• Explain how vitamin D, sodium, caffeine, and alcohol affect calcium levels in the body.
• List the best sources of calcium in addition to dairy products and calcium supplements.
• Explain how weight-bearing and/or resistance exercises protect and strengthen bones.
• Understand how long-term use of glucocorticoids can increase the risk of developing osteoporosis.
• Understand how hormone replacement therapy (HRT) can treat and/or prevent osteoporosis.
• Know the pros and cons of HRT as well as options other than HRT for the treatment of osteoporosis.

Osteoporosis; calcitonin; calcium; bone; homeostasis; hormone replacement therapy; HRT; parathyroid hormone; PTH; endocrine system

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High school, Undergraduate lower division, General public & informal education

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Patient Case Presentation

Mrs. C.R. is a 74-year white female presenting with mid to low back pain x 2 weeks.  She reports feeling the pain after picking up her 2-year-old great granddaughter while participating in a family garage sale.  Pain increases with movement and positioning. Heat and ibuprofen provides no relief.  She incidentally reports a noticed “shape change” to her back.

Medical History

• Breast cancer at age 70, treated by doxorubicin chemotherapy and radiation
• Back injury from MVA in 20s
• Hypothyroidism
• Frequent UTIs, last infection 2 weeks prior

Medications : 

• Levothryoxine

Surgical History

• TAH-BSO due to uterine fibroids at age 45 with 2 years of hormone replacement therapy
• Cholecystectomy

Family History

• Mother deceased, history of Parkinson Disease
• Father deceased, history of colon polyps and diabetes
• Brother alive, history of diabetes
• Brother deceased, history of diabetes
• Brother deceases, history of diabetes and stroke
• Brother alive, history of diabetes and COPD
• Sister alive, history of premature menopause, diabetes, and breast cancer at age 78

Social History

• Hobbies include quilting, sewing, and embroidery

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• Meat cutter

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Real-World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe

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• Yamei Wang PhD 1 ,
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Real-World Evidence (RWE), which has historically been used to support post-approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here, we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post-marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review of the initial MAA submitted in 2015. However, these studies taken together with the RWE formed the basis for a new MAA. Prior to the planned resubmission in the EU, national Scientific Advice (SA) was sought on the proposed clinical program, specifically on the relevance of Real-World Data (RWD) derived from an observational study to support and complement the efficacy and safety data already available from prospective randomized clinical trials. This case study demonstrates successful use of RWE to address a previously identified gap raised by the CHMP during the review of an earlier MAA, which led to the approval of Eladynos for the treatment of osteoporosis in the EU.

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Introduction

Randomized controlled trials (RCT) are the gold standard for the assessment of clinical efficacy and safety in regulatory decisions. However, the ability to fully characterize the safety of a new medicinal product in the limited setting of a controlled trial has led to the collection of patient data from post-approval safety surveillance programs for decades. Over time, the value of this “real-world” data (RWD) beyond pharmacovigilance studies has increasingly been recognized and includes data derived from electronic health records, disease registries, and patient surveys. Clinical evidence about the benefits and risks of a medicinal product derived from RWD is referred to as Real-World Evidence (RWE). More recently, regulators have considered RWE in the context of their benefit–risk evaluation of new products and/or indications, but mostly for drugs with orphan drug designations and/or in disease areas with high unmet medical need [ 1 ]. In the first part of this article, an overview of the current regulatory RWE framework and existing guidance in the EU is presented followed by a case study for which RWE was used to address concerns regarding the safety and efficacy of abaloparatide for the treatment of osteoporosis in postmenopausal women at increased risk of fracture following a previously rejected application.

Use of Real-World Data/Real-World Evidence in EU Medicines Regulation

The European Medicines Agency (EMA) works together with the Heads of Medicines Agencies (HMA) to form a European medicines regulatory network that focuses on the development, co-ordination, and consistency of the European medicines system while addressing key strategic initiatives for the network. To this end, the EMA and HMA have issued strategic 5-year roadmaps/network strategies that identify shared challenges, goals, and priorities, to ensure the continued success of the European medicines regulatory network since 2005. A key goal of each of these 5-year roadmaps is to further strengthen the protection of human health while encouraging and facilitating innovation and research in the EU (see Table  1 ). The first Roadmap focused on strengthening and operationalizing the partnership of all the EU regulatory authorities, introduction of new legal tools to accelerate patient access to medicine and creation of a robust pharmacovigilance system across the EU (see Table  1 ). The concept of real-world use of medicines first appeared in the “Roadmap to 2015” published in 2010. A key strategic priority included in this roadmap focused on minimizing the risks to public health when using newly approved medicines in a “real-world” setting by building on the pharmacovigilance platforms introduced in the “Roadmap to 2010” (see Table  1 ). Real-world data from registries, claims, and electronic health records were some of the initial resources used in post-marketing pharmacovigilance activities such as signal detection, validation, and assessment.

Early in 2019, the HMA-EMA Joint Big Data task force published recommendations supporting acceptability of evidence derived from “Big Data” [ 2 ] (see Table  1 ). Big data consist of large and often complex datasets that tend to be both unstructured and heterogeneous. Big data accumulate rapidly and need to be analyzed computationally to reveal patterns, trends, and associations. The currently established regulatory framework is based on the assessment of data from well-controlled, randomized clinical trials designed to provide unbiased estimates of efficacy and safety. Therefore, the introduction of big data required thoughtful assessment of when and how such data may be considered for regulatory decision making in the product life cycle. The initial priority of the task force was to develop global standards for data quality and methodology for the use of big data in regulatory decision making.

By 2020, big data had become part of the current regulatory environment necessitating regulators to address challenges arising from collecting and processing such data (see Table  1 ). The EMA’s Data Analysis and Real-World Interrogation Network (DARWIN EU) was created to provide timely and reliable evidence on safety and effectiveness of medicines for human use using real-world healthcare databases across the EU. The objective of DARWIN EU is to facilitate the exchange of healthcare data for use in research, regulatory policy making, and healthcare delivery in Europe. The DARWIN EU® Advisory Board, formed in June 2021, brings together a federated network of data partners from public or private, regulators, patients, health technology assessment (HTA) bodies, and payers. Erasmus University Medical Centre based in Rotterdam, Netherlands was selected in February 2022 as the service provider to deliver DARWIN EU.

The network completed its first four studies in 2022, and the EMA is planning between 10 and 15 studies in 2023, and around 150 per year from 2025 [ 7 ]. The protocols and results of these studies are publicly available in the EU PAS (Post-Authorisation Studies) Register ( https://www.encepp.eu/encepp/studiesDatabase.jsp ). Once fully operational, DARWIN will answer questions posed by EMA’s scientific committees and National Competent Authorities to better understand diseases, populations and the use, safety, and effectiveness of medicines. The EMA recently issued a report on the experience gained from regulator-lead real-world studies from September 2021 to February 2023 [ 8 ]. To determine the impact of these studies on regulatory decision making, the EMA conducted a survey of the regulators requesting the studies and of the 18 responses, 12 of these studies were considered supportive [PRAC review of safety signals and PSURs ( n  = 7), scientific advice requests ( n  = 3), and PDCO decisions on PIP/waiver requests ( n  = 2)].

Currently the EMA is working to develop a data quality framework for all data used in regulatory decision making including RWD [ 1 ]. The EMA is also evaluating the evidentiary value of RWE and emphasizes a complementary evidence approach with a place for both RCT and RWE to be used in conjunction rather than in opposition. EMA’s vision is that by 2025, the use of RWE across a spectrum of regulatory use cases will have been realized. While broad use of RWE in regulatory decision making is not yet a reality, use of RWE to support safety of drugs and more recently initial marketing authorizations have been observed. Flynn et al. reported for new MAA submitted in the EU (centralized procedure) between 1 January 2018 and 31 December 2019, 63 of 158 (39.9%) of initial applications contained RWE and approximately one third of these applications included RWE collected prior to the planned authorization [ 9 ]. These RWDs were primarily from registry (60.3%) and hospitals data (31.7%) and were mainly included to support safety (87.3%) and efficacy (49.2%). The most common study design was a cohort study (87.6%). Bakker et al. further characterized this dataset but focused on MAAs in which the RWE contributed to the efficacy/effectiveness data [ 10 ]. Of the 63 MAAs with RWE, 32 (50%) included RWD related to efficacy/effectiveness outcomes and disease epidemiology. Two thirds of those applications were for products with orphan designation and were primarily for indications with high unmet medical need. From the compilation of MAAs submitted between 2018 and 2019, only 3% (5/158) contained RWE collected prior to the authorization and for which the submitted efficacy data were considered by the CHMP as supportive for their regulatory decision making. These 5 medicinal products included onasemnogene abeparvovec (Zolgensma), trientine dihydrochloride (Cufence), melphalan (Phelinun), and hydroxycarbamide (Xromi). The fifth product was for a rare thromboembolic disorder and was withdrawn. A few details from the European Public Assessment Reports (EPAR) on how the CHMP relied on the RWE for regulatory decision making for these products are provided below.

Two of these products (melphalan and hydroxycarbamide) were submitted as hybrid applications and relied on nonclinical and clinical data from a reference product already approved in the EU. Mephalan is a cytotoxic agent that works by preventing cell division. To support the new indication, use as a conditioning treatment prior to allogeneic hemopoietic stem cell transplantion, the sponsor reviewed safety and efficacy data from 18 peer-reviewed articles published between 2005 and 2018 including 3096 patients from both interventional and observational studies. Similarly, hydroxycarbamide had a well-established safety and efficacy profile as it had been used in the EU for many years. A literature review containing real-world studies with effectiveness and safety data was considered adequate to support the indication for the prevention of vaso-occlusive complications of sickle cell disease. The other two products (onasemnogene abeparvovec and trientine dihydrochloride) were for orphan diseases. Onasemnogene abeparvovec initially received conditional approval for treating spinal muscular atrophy. The pivotal Phase 3 study included a single arm and relied on a natural real-world historical cohort control (external comparator) for demonstration of efficacy. Of note, the use of a historical comparator from the natural history study was agreed upon during a scientific advice meeting. During the MAA review, the CHMP considered the historical comparator adequate owing to the similar timing of outcome/endpoint assessment in the Phase 3 study compared to the natural real-world history cohort, and to the homogeneity of the cohorts. The safety was augmented by inclusion of post-marketing experience from the US and France including 192 cases. A Post-Approval Efficacy Study was required as a condition for approval. Trientine dihydrochloride was submitted as a full mixed marketing application. The primary safety and efficacy data were derived from a Phase 4 real-world study that reviewed the medical records from 77 patients. In addition, trientine had been used for over 30 years to treat Wilson Disease and a review of literature provided additional supportive information. During the MAA review, several methodological shortcomings were identified by the CHMP (e.g., lack of controls, blinding/randomization, lack of sample size calculation, lack of definition of the primary endpoint), but these did not prevent the approval of the product considering the totality of the evidence provided on the efficacy and safety.

A recent paper outlines the benefits and limitations of RWE studies and how to ensure that transparent and high-quality evidence is generated, with a focus on osteoporosis research [ 11 ].

A Case Study is presented in the following section for which regulators considered RWE in the context of their benefit–risk evaluation of a new medicinal product for osteoporosis.

Osteoporosis and Available Therapy

Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture [ 12 , 13 , 14 ]. The main characteristics of osteoporosis are low bone mineral density (BMD) and fractures. Two classes of therapies for treatment of osteoporosis are currently available in the EU, the antiresorptives (bisphosphonates and denosumab) and those with anabolic activity (teriparatide, abaloparatide, and romosozumab). Antiresorptives increase BMD by reducing the ability of osteoclasts to resorb bone, while the anabolic drugs act on osteoblasts to build new bone.

Abaloparatide is a synthetic 34 amino acid peptide that shares 41% homology to parathyroid hormone [PTH(1–34)] and 76% homology to parathyroid hormone related peptide [PTHrP(1–34)] and is a potent and conformation specific activator of the PTH1 receptor signaling pathway. Once daily administration of abaloparatide stimulates new bone formation on trabecular and cortical (periosteal, intercortical, and endocortical) bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. Teriparatide (trade name Forsteo in the EU and Forteo in the US), a recombinant human parathyroid hormone peptide (rhPTH1-34), is the closest comparator to abaloparatide and was used as the active comparator (open-label) in the pivotal registration placebo-controlled Phase 3 study (BA058-05-003; ACTIVE) [ 15 ].

The development of abaloparatide for the treatment of osteoporosis in postmenopausal women followed the recommendations set forth in the Guideline on the Evaluation of Medicinal Products in the Treatment of Primary Osteoporosis [ 16 ]. Consistent with the Guideline, SA provided before the initial MAA emphasized the need to show efficacy on both vertebral and nonvertebral fractures. Also, consistent with CHMP’s guidance on having a single Phase 3 study, the results from a single pivotal trial would need to be compelling. The pivotal study establishing the efficacy and safety of abaloparatide in postmenopausal women with osteoporosis was Study BA058-05-003 (ACTIVE) which was a randomized, double-blind, placebo-controlled, comparative Phase 3 multicenter study conducted in ambulatory postmenopausal women with osteoporosis and at risk for fracture [ 15 ]. The key efficacy endpoints in the ACTIVE study included the incidence of new vertebral and nonvertebral fractures with abaloparatide versus placebo following 18 months of treatment.

Timelines for Regulatory Approval in the US and EU

The timelines for the submission and approval of the marketing authorization applications for abaloparatide in the US and EU are presented in Fig.  1 .

Timelines for Regulatory Approval in the US and EU.

Abaloparatide was approved in the US on 28 April 2017 under the tradename of Tymlos and is indicated for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture), or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, Tymlos reduces the risk of vertebral fractures and nonvertebral fractures. Abaloparatide was also recently approved by the FDA on 19 December 2022 as a treatment to increase bone density in men with osteoporosis at a high risk for fracture [ 17 ]. Abaloparatide was also approved in Japan on 23 March 2021 under the tradename of Ostabalo® for the treatment of male and female patients with osteoporosis who are at high risk for fracture.

On 17 November 2015, Radius International Ltd submitted an MAA for abaloparatide through the centralized procedure and received a negative opinion during the March 2018 CHMP meeting. A re-examination procedure started on 29 May 2018 and ended on 26 July 2018 with the refusal of the granting of the Marketing Authorization. The total review period of this dossier was 2 years and 7 months (from 4 December 2015 to 26 July 2018). There were two primary reasons for the overall negative benefit-risk assessment. First, only one pivotal study (BA058-05-003; ACTIVE) was conducted and due to serious Good Clinical Practice-related concerns associated with a single Principal Investigator, data from two sites were excluded, reducing the size of the study population by 16%. Consequently, the study failed to demonstrate a statistically significant effect on nonvertebral fractures (NVF) versus placebo. As shown in Table  2 , abaloparatide did significantly reduce the frequency of NVF as compared to placebo following 18 months of treatment based on the full dataset. However, the sponsor agreed with the CHMP to exclude the data from these 2 clinical sites from the MAA.

The totality of evidence included in the MAA supported that abaloparatide is effective in preventing nonvertebral fractures. Abaloparatide demonstrated trends toward the reduction of nonvertebral fractures (26%) and major nonvertebral fractures (46%), and abaloparatide significantly reduced major osteoporotic fractures by 69% ( p  = 0.004) versus placebo. An extension study was performed in which abaloparatide- or placebo-treated subjects from the ACTIVE study were treated with alendronate for an additional 2 years (Study BA058-05-005; ACTIVExtend) [ 18 ]. At 25 months, following 6 months of treatment with alendronate, subjects previously treated with abaloparatide (abaloparatide/alendronate) demonstrated a trend toward reducing nonvertebral fracture (48%), a significant 58% reduction in major nonvertebral fractures ( p  = 0.031), and a significant 63% reduction in major osteoporotic fractures ( p  = 0.017) versus placebo-treated subjects (placebo/alendronate). At 43 months (18 months of treatment with alendronate), abaloparatide/alendronate demonstrated a trend toward reduced nonvertebral fracture (39%), significantly reduced major nonvertebral fractures by 54% ( p  = 0.014), and significantly reduced major osteoporotic fractures by 52% ( p  = 0.024) versus placebo/alendronate. However, the failure to demonstrate a statistically significant effect on NVF versus placebo remained a major objection. The second major objection raised by the CHMP was related to concerns about potential safety risks associated with transient and reversible heart rate increases with abaloparatide compared to teriparatide and placebo. Because the pivotal study included relatively healthy ambulatory postmenopausal women free from significant cardiac disturbances, the data from the study were considered insufficient for assessing a risk for adverse cardiovascular outcomes potentially associated with transient increase heart rate in a generally more vulnerable real-world osteoporosis population of patients.

Since this initial application, new clinical data have been acquired via the conduct of additional interventional and observational studies, as well as post-marketing data obtained from the US market since approval of abaloparatide on 28 April 2017 (see Fig.  2 ).

New Efficacy, Effectiveness, and Safety Data Address Concerns Raised from Prior EU MAA Review.

These data included (1) a dual-energy X-ray absorptiometry (DXA)-3D-based modeling study (post-hoc analysis in a sub-population of the ACTIVE study [ 19 ]) to further differentiate the effects of abaloparatide on hip cortical volumetric BMD and estimated hip strength; (2) a histomorphometry study in women with osteoporosis (BA058-05-020) that further demonstrated the mechanistic action and anabolic effect; (3) a Japanese Phase 3 bridging study providing additional safety and efficacy data and further understanding of the effects on hip biomechanical properties (ITM-058-301); (4) a retrospective observational cohort study (BA058-05-028) using data from the Health Claims database (Symphony Health Integrated Dataverse (IDV)®) with a pre-specified protocol and statistical analysis plan demonstrated that abaloparatide was comparable to teriparatide for prevention of NVF, resulted in a 22% risk reduction for hip fractures, and demonstrated similar cardiovascular safety following 18 months of treatment [ 20 ]; and (5) post-marketing surveillance information from the US demonstrating no cardiovascular safety signal. These data enhanced the understanding of abaloparatide’s mode of action in humans and provided additional evidence on the safety and efficacy of abaloparatide to reduce fracture risk at both vertebral and nonvertebral sites.

Prior to the planned resubmission in EU, Radius obtained national SA from countries that previously had both positive and negative assessments for the initial MAA including MPA/Sweden (28 January 2021), AGES/Austria and BfArM/Germany (17 February 2021), Lithuania (17 March 2021), NoMA/Norway (18 March 2021), SNS/Portugal (8 April 2021), FAMHP/Belgium (13 April 2021), and AEMPS/Spain (26 April 2021). The goal for the SA was to obtain feedback on the proposed overall clinical program to be used for the new MAA submission, specifically on the relevance of real-world data collected in a proposed retrospective study to support the efficacy and safety assessment of prospective clinical trials. A summary of the key points raised during these meetings is summarized in Table  3 .

Most agencies were supportive of a new MAA submission and considered RWE an important part of the dossier. There was no doubt that abaloparatide had an anabolic effect on bone, but the question remained whether this would translate into a clinical effect on reduction of NVF. The SA was divergent on whether data from an observational cohort study could provide adequate evidence that abaloparatide decreased the risk of NVF; and in the absence of conducting a second RCT, it was clear that this would be a critical review issue.

The sponsor included a justification in the MAA for why a second RCT was not performed. This justification was based on the totality of information collected with abaloparatide (pivotal and supportive studies; see Fig.  2 ) as well as the knowledge of the effects of teriparatide (same molecule class, same mode of action). The pivotal ACTIVE study demonstrated that treatment with abaloparatide resulted in a significant reduction in VF versus placebo and a consistent trend in favor of reduction of NVF. There was no scientific reason to presume efficacy only for VF and not on NVF, especially considering the relevant increases in BMD observed at the lumbar spine, hip, and femoral neck. Therefore, considering all the available data, the sponsor considered it inappropriate to conduct a second placebo-controlled study in subjects at high risk for fracture but worked with the health authorities to prospectively design an observational study to support the comparable effectiveness of abaloparatide versus teriparatide of NVF rate in high-risk patients, and to corroborate the findings of the pivotal ACTIVE study.

Regarding safety, several of the agencies indicated that it would be important to include data on mortality as part of the observational study. It was also highlighted that it was important to present not only the major adverse cardiovascular event (MACE) data but also data on tachycardia and arrhythmia. Because the main safety concern with abaloparatide would be for patients with high or very high CV risk, it was recommended to look at these subpopulations. Regarding the observational study, advice also stressed the importance of providing all protocols and planning documents to avoid any concern that the research approach was data driven. The dossier should include all the information available to support that the analyses had been pre-specified.

Sensitivity analyses were requested to demonstrate the stability of the propensity score-matched cohorts, and to evaluate the impact of prior non-anabolic treatments and duration of anabolic treatment on the effectiveness and safety endpoints. For cardiovascular safety evaluation, sensitivity analyses were also requested to test the robustness of findings by baseline CV risk factors given the high prevalence of these risk factors in the target population. During the review of the MAA, the CHMP requested additional sensitivity analyses including the original data without propensity score matching, propensity score stratification, and inverse probability of treatment using the propensity score and multivariable regression model to the original data adjusting for all confounders. The CHMP also requested Intention-To-Treat (ITT) analysis for safety endpoints, and an As-Treated (AT) analysis for effectiveness evaluation.

A discussion of the strengths and limitations of RWE was also requested during scientific advice.

Study BA058-05-028: A Retrospective, Observational Cohort Study Evaluating the Effectiveness of Cardiovascular Safety of Abaloparatide in Postmenopausal Women New to Anabolic Therapies

A retrospective observational cohort study was conducted using anonymized patient claims data from PRA Health Science’s Symphony Health Integrated Dataverse (IDV) database including the enhanced hospital data (NCT04974723). The goal of this observational study was to evaluate the comparative effectiveness and cardiovascular safety of abaloparatide versus teriparatide for the treatment of osteoporosis in postmenopausal women in the real-world healthcare setting in the US. The methodology and results from this study have been previously published and are briefly summarized below [ 20 ].

Data for this study included routinely collected information in healthcare encounters from all available healthcare settings (inpatient hospital, outpatient hospital, physician office, pharmacy, etc.) for all types of provided services including specialty, preventive care, and office-based treatments. Since this was not a randomized study, patients were matched using an extensive list of indicators of disease severity and fracture risk, including fracture and treatment history as per evidence-based clinical practice guidelines [ 22 ] by logistic regression-based propensity score (PS) matching in order to ensure that the two cohorts were comparable in their probability of receiving and benefiting from treatments. A total of 11,027 patients were included in both the abaloparatide and teriparatide groups. The post-index treatment period consisted of the 18 months after the index date (date initial prescription dispensed) with the maximum evaluation period of 18 months plus 30 days of follow-up (19 months), to be consistent with the pivotal Phase 3 study (ACTIVE).

The primary analyses of effectiveness were based on the time to first incidence of NVF. From a clinical perspective, any reduction in risk of NVF versus placebo that is greater than 25% is clinically important since this would indicate an improvement in the effect for bisphosphonates, as seen in the HORIZON trial [ 23 ]. Overall, 313 (2.8%) patients in the abaloparatide cohort and 333 (3.0%) patients in the teriparatide cohort had a NVF. The risk of new NVF from the index date was similar between the abaloparatide and teriparatide groups [HR (95% CI) 0.94 (0.81, 1.10)]. With regard to hip fractures, 112 (1.0%) and 125 (1.1%) patients in the abaloparatide and teriparatide cohorts, respectively, had a hip fracture. The risk of new hip fractures from the index date was similar between the two cohorts [HR (95% CI) 0.90 (0.69, 1.16)].

Cardiovascular safety was evaluated by examining the time to first incidence of a composite endpoint of MI, stroke, and hospital CV death, with and without inclusion of heart failure. The incidence of the composite endpoint of MI, stroke, and hospital CV death was similar in abaloparatide and teriparatide-treated cohorts (2.0% and 1.9% with abaloparatide and teriparatide, respectively, [HR (95% CI) 1.08 (0.89, 1.30)], as was the incidence of the composite endpoint of MI, stroke, heart failure, and CV death (4.5% and 4.3% with abaloparatide and teriparatide, respectively, [HR (95% CI) 1.08 (0.95, 1.22)]). The individual events of MI, stroke, heart failure, hospital CV death, and hospital all-cause death also occurred with similar frequency between the abaloparatide and teriparatide-treated cohorts.

The observational RWE study had several strengths allowing for a robust comparative assessment of treatment effectiveness and safety. The data are representative of a broad population of patients including those with more CV risk factors compared to the subjects included in the randomized controlled pivotal Study BA058-05-003. Because there are no restrictions for CV disease in the US labeling for abaloparatide (Tymlos), approximately 76% of patients in the BA05-05-028 study had CV risk factors and approximately 10% of patients had a prior event of MI, stroke, or heart failure. In addition, data were from multiple payers and geographically diverse settings across the US and captured over 90% of pharmacy claims in the US. The prescription claims were for prescriptions filled, not prescriptions written. As such, the findings from the study were expected to have a high generalizability. A claims-based fracture incidence algorithm, which has a high specificity and has been shown to have over 90% accuracy based on positive predictive value in previous studies [ 24 ], was used to assess fracture events. In addition, because over 11,000 patients were included in each cohort, a much larger number of NVF were observed in the BA058-05-028 study as compared to the pivotal BA058-05-003 study.

CHMP Review of 2021 MAA

Following receipt of the D120 List of Questions (LoQ), it was clear that the original evidence gap regarding effect of abaloparatide on NVF had been addressed. While it was pointed out that the effect of abaloparatide versus placebo on NVF was not statistically significant in the pivotal Phase 3 ACTIVE study, the data were indicative of a trend in favor of abaloparatide. Regarding the fact that a second pivotal study was not conducted, the CHMP reviewers considered that the additional data submitted including a placebo-controlled Phase 3 bridging study in Japan, a histomorphometry study in patients confirming the anabolic mechanism of action, and new post-hoc analyses of the hip DXA images from the ACTIVE study providing data on hip cortical volumetric BMD and estimated hip strength to be supportive of efficacy. The CHMP also considered the NVF data from the > 22,000 patients included in the RWE observational cohort study including more than 646 NVF to be supportive. The CHMP raised several concerns related to the conduct and analysis of this observational study and requested several sensitivity analyses to be conducted. The CHMP stated in the EPAR that while “there were important limitations in the design of the observational study, the main analyses as well as several sensitivity analyses support comparable effectiveness versus teriparatide in a US population to a degree that indicates superiority to a putative placebo.”

Regarding safety, the Day 120 LoQ included one major objection regarding the potential risk of serious cardiovascular events due to the transient increase in heart rate with abaloparatide compared to placebo. The CHMP acknowledged that this MAA included post-marketing data from the US covering 47,618 patient-years of treatment and that no signal for MACE had been observed. Due to the outstanding questions related to the conduct and analysis of the observational study, the reviewers could not conclude if these data would address the remaining issue of cardiovascular safety.

The sponsor submitted a response to the Day 120 LoQ including safety data from a recently completed Phase 3 study in men with osteoporosis (BA058-05-019) as well as the requested sensitivity analyses for the observational RWE study. In the Day 180 List of Outstanding Issues (LoOI), the Major Objection had been resolved. In the EPAR, the CHMP indicated that the Japanese bridging study and new histomorphometry study did not provide any additional insights in the cardiovascular safety of abaloparatide. Data from Study BA058-05-019 suggested that men and women treated with abaloparatide had a similar frequency and pattern of CV events with no new safety concerns being identified. Regarding the observational study (BA058-05-028), the CHMP stated that “that the MACE (MI/Stroke/heart failure/hospital CV death) event rates were not significantly increased in abaloparatide treated patient compared to teriparatide.” The CHMP cited the main study limitations to be the absence of mortality data recorded outside of hospitals, lack of access to income and education data, and potential bias caused by difference in price between abaloparatide and teriparatide (abaloparatide is less expensive). In the EPAR the CHMP stated, “the new data has not confirmed that increases in heart rate associated with abaloparatide would be associated with increase of serious CV events. However, both the observational study and post-marketing data have important limitations. Still, for a majority of osteoporosis patient, abaloparatide is well tolerated and the safety seems acceptable.”

The ongoing concern that patients with untreated heart disease or rhythm disturbances may still be at risk of serious adverse events was to be addressed in the labeling and the eventually agreed upon Post Authorization Safety Study (PASS). On 12 December 2022, the EU granted marketing authorization of abaloparatide under the tradename of Eladynos® to treat osteoporosis in postmenopausal women at increased risk of fracture. On 27 March 2023, the Medicines & Healthcare products Regulatory Agency (MHRA) approved Eladynos® for the same indication in the Great Britain under the European Commission Decision Reliance Procedure.

This case study is one of the first examples of RWE used to support the approval of a new medicinal product in the EU for a disease state not considered to have high unmet medical need and a non-orphan indication. The CHMP assessed data from a single pivotal Phase 3 study, clinical data from additional interventional and observational studies, as well as post-marketing data obtained from the US since the approval of abaloparatide in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review of the initial MAA submitted in 2015. However, data from the observational study addressed the previous CHMP concern regarding the effectiveness of abaloparatide to treat osteoporosis in postmenopausal women with an acceptable cardiovascular risk profile. This study was designed in accordance with available FDA and EMA guidance and SA from eight national Health Authorities in which the decision makers’ perspective on the robustness of the source of data, methodology, and addressing biases associated with real-world study design were considered.

While RWE studies are not meant to replace RCT, fit-for-purpose data can be used as supporting evidence when conduct of an additional RCT is not feasible or is unethical. Due to the totality of the available efficacy data for abaloparatide, the sponsor considered conducting a second placebo-controlled study to generate additional efficacy data based on a reduction in the incidence of NVF to be impractical and possibly unethical in subjects at high risk for fracture. An important advantage of observational studies is the inclusion of a larger population of patients than normally seen in a RCT and a larger number of events of interest. Indeed, the observational study that demonstrated comparable effectiveness between abaloparatide and teriparatide included more than 22,000 patients with almost 650 NVF. Abaloparatide and teriparatide are both anabolic drugs that stimulate new bone formation following binding to the PTH1 receptor. As stated in the EPAR, the CHMP considered that the data from the observational study to support comparable effectiveness versus teriparatide to a degree that indicated superiority to a putative placebo. An additional advantage of the observational study is that the evaluation of safety outcomes is not restricted to a small population of patients with few comorbidities as in the RCT. The CHMP had considered the pivotal Phase 3 ACTIVE study insufficient for assessing CV risk potentially associated with transient increase in heart rate because subjects were primarily healthy ambulatory postmenopausal women free from significant cardiac disturbances. In the EPAR, the CHMP indicated that while the new post-marketing and observational data did not confirm that increases in heart rate were associated with an increase of serious CV events, the safety seemed to be acceptable for a majority of osteoporosis patients.

It is unusual for RWE to support approval of a new indication since real-world data are not available until after regulatory approval and market access. However, in the current case study, abaloparatide was approved previously in the US, where more than 5 years of real-world data had been accumulated and were available for research. Furthermore, an argument was made for the generalizability of the findings from the US to the EU population based on comparative epidemiology, treatment patterns, and global clinical practice guidelines [ 22 , 25 , 26 ]. In addition, data from the pivotal Phase 3 ACTIVE study showed that pharmacokinetics and pharmacodynamics were not different between EU and US regions, and intrinsic factors such as age, race, region, weight, prior fracture, and severity of disease did not affect efficacy or safety of abaloparatide with similar results seen across the four geographies including the US and EU.

Despite the above argument, the CHMP still considered there to be a limitation of using data from one country for another due to differences in health care delivery and potential differences in the abaloparatide target population characteristics between US and EU populations (e.g., age, severity of disease). A post-marketing study using European registries to assess CV risk was considered to be feasible as such studies had previously been performed for other osteoporosis medicines. The CHMP believed that such a Post-approval Safety Study (PASS) may provide a more comprehensive safety dataset including all-cause mortality data. Therefore, a PASS was proposed as part of the Risk Management Plan for Eladynos in the EU.

Since the early use of RWE in the post-approval safety space, RWE has more recently been accepted as supporting evidence in the benefit–risk evaluation of new indications or even initial approval of new medicinal products by global health authorities. The usefulness of RWD for regulatory decision making is dependent on data quality, pre-specification, and transparency of methodology, consideration of methodological approaches to minimize bias, and early discussions with health authorities to ensure that the data are fit for purpose. Flynn et al. [ 9 ] and Bakker et al. [ 10 ] described use of RWE in regulatory decision making for new MAAs submitted via the centralized procedure between 1 January 2018 and 31 December 2019. Most of these applications were for indications of high unmet need or orphan designation. In a recently issued report from the EMA [ 8 ] on regulator-led real-world studies, safety evaluation was the most cited utility of such data for the regulatory review. The case study presented here is unique because the RWE was used to support the initial approval of a new medicinal product for osteoporosis in the EU. Another recent regulatory case study [ 27 ] described a retrospective cohort study used to demonstrate that the effectiveness and safety of denosomab (tradename Prolia) in Chinese women living in Taiwan and Hong Kong was comparable to the data from the global Phase 3 pivotal fracture study (FREEDOM) leading to the initial approval of denosomab in China.

In conclusion, the EMA is increasingly considering RWE in their review of MAAs and in the case of abaloparatide, the EMA recently considered the totality of evidence in a newly submitted MAA, which included data from a prospectively planned retrospective observational cohort study, leading to the approval of a new medicinal product for osteoporosis. This regulatory case study demonstrated that with early scientific advice, it is possible to use real-world data to address previously raised concerns regarding benefit–risk leading to approval of a new medicinal product for an indication not associated with an orphan designation or high unmet need in the EU.

Data availability

The source data for this study were licensed from a third party, by Radius Health, Inc (Radius). Although we are not permitted to share the licensed data publicly, the same data used in this study are available for others to license by contracting with the database owners. Radius licensed data from Symphony Health, Integrated Dataverse (IDV)®, May 2012 to January 2021, which included anonymized patient level data from pharmacy claims linked to commercial and Medicare medical claims data. Symphony Health licensing information can be found at www.symphonyhealth.com with the database owners. The authors did not have any special access privileges that other parties who license the data and contract with Symphony would not have.

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YW, BM and SAW contributed to the design, conduct, and analysis of Study BA058-05-028. CD, PG, and AW contributed to the regulatory strategy. All authors were involved in the preparation and review of the MAA.

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Colleen Davenport, Bruce Mitlak, and Yamei Wang are employees of Radius Health. Setareh Williams is a former employee of Radius Health and continued to support Study BA058-05-028 and the Marketing Authorization Application as a paid consultant after she had left the company. Both Alethea Wieland and Patricia Gravel supported the MAA as paid consultants.

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Davenport, C., Gravel, P., Wang, Y. et al. Real-World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe. Ther Innov Regul Sci (2024). https://doi.org/10.1007/s43441-024-00616-7

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Educational Case: Osteoporosis

Jonathan light.

a School of Medicine, Eastern Virginia Medical School, Norfolk, VA, USA

Harrison Klause

b Department of Radiology, Eastern Virginia Medical School/Medical Center Radiologists, Norfolk, VA, USA

Richard M. Conran

c Department of Pathology & Anatomy, Eastern Virginia Medical School, Norfolk, VA, USA

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see https://www.journals.elsevier.com/academic-pathology/news/pathology-competencies-for-medical-education-pcme . 1

Primary objective

Objective MS2.3: Osteoporosis. Distinguish primary from secondary osteoporosis in terms of etiology, pathogenesis, and morphology.

Competency 2: Organ System Pathology; Topic: MS: Musculoskeletal System; Learning Goal 2: Nonneoplastic Disorders of the Musculoskeletal System.

Patient presentation

A 76-year-old woman is brought to the emergency department (ED) by ambulance with an externally rotated, abducted, and shortened left lower extremity. The patient says she fell out of bed and could not get up. Prior to the fall, she states she did not have any head trauma, preceding syncopal events, or a history of falls. Her past medical history includes restrictive lung disease for several years but no recent hospitalizations. She has no allergies to medications and has never had an adverse drug reaction. Her only recent medication is bisphosphonate anti-resorptive therapy for a previous vertebral fracture (eight years ago), and she has been on a drug holiday for three years after five years of treatment. Her age of last menstruation was 51 years. Her family history includes lung cancer in her father. There is no family history of hip fracture. She does not smoke, use alcohol, or have a hazardous occupational exposure. Her diet has not recently changed, and there is no recent weight loss. She lives with her daughter and son-in-law and is minimally active, rarely getting sunlight. The review of systems is negative for recent headache, migraine, fevers, cough, urinary changes, hematochezia, melena, or abdominal pain. In the ED, she receives 2.5 mg morphine, intramuscular (IM), on arrival for pain, and is placed on 100% oxygen for some difficulty breathing.

Diagnostic findings, Part 1

The patient's height is 61 inches (154.94 cm), and she weighs 122 pounds (55.34 kg). Her vital signs are blood pressure 148/78 mmHg, heart rate 110 beats per minute, respiratory rate 20 breaths per minute, and temperature of 98.2 °F. Oxygen saturation by pulse oximetry is 88% on room air. Head, ears, eyes, neck, and throat (HEENT) examination demonstrates no head trauma, dry mucous membranes, no palpable thyroid nodules, or glandular enlargement or atrophy; otherwise, the HEENT examination is normal. There is a small abrasion on the left hip, approximately 3 cm in diameter, and ecchymosis with significant swelling of the affected joint; otherwise, the dermatologic examination is unremarkable. Her cardiac examination reveals tachycardia and normal S1, S2 sounds with no rubs, gallops, or murmurs. Her lungs are clear on auscultation, but she is short of breath with tachypnea. Her abdominal examination demonstrates slight protrusion, normal bowel sounds, and no palpable masses or organomegaly. Her musculoskeletal examination demonstrates severe kyphoscoliosis with some tenderness to palpation over the lumbosacral vertebrae. Her left lower extremity is externally rotated, abducted, and shortened. The distal pulse of the left lower limb is 2+ (normal 3+). Her musculoskeletal examination of the right lower extremity is unremarkable, with normal distal pulse 3+, normal range of motion, and strength of 5/5. She has no focal neurologic deficits.

Questions/discussion points, Part 1

What is the significance of the decreased distal pulse.

The decreased distal pulse indicates impaired blood flow, which is concerning for torn retinacular arteries, branches of the medial circumflex femoral artery, and the major blood supply of the femoral head. Avascular necrosis of the femoral head should be a clinical consideration in this scenario as it is common in hip fracture. 2

What is the differential diagnosis for the patient?

The differential diagnosis includes hip fracture, hip dislocation, osteoporosis with secondary kyphoscoliosis, osteomalacia, vertebral fracture, and cancer, including metastatic bone disease and multiple myeloma. Hip fracture is ranked high on the differential, but the patient's history and physical examination (PE) cannot exclude an underlying cause, such as metastatic bone disease or osteoporosis. Furthermore, understanding the cause of the patient's fall is prudent for a complete assessment and management to identify any underlying medical conditions.

Define osteomalacia, osteopenia, and osteoporosis and discuss how each of these entities potentially relates to the patient

Osteomalacia is an impairment of bone matrix (osteoid) mineralization in adults, which can only be definitively diagnosed by bone biopsy. 3 , 4 , 5 Osteomalacia is typically caused by a deficiency in vitamin D or a defect in its metabolism. 3 Bone that undergoes remodeling and is undermineralized in osteomalacia predisposes to fracture, which may be the cause of the patient's presentation. 3 Radiographs demonstrating proximal femur pseudofractures and osteopenia are sometimes observed in osteomalacia. 4 Since the patient's history is significant for rare sunlight exposure, vitamin D deficiency is possible. Osteopenia, a decreased bone mass, may be caused by osteomalacia. Osteopenia, if significant enough to increase fracture risk, is termed osteoporosis. 3

Osteoporosis has normal bone mineralization but reduced bone mass. 3 , 6 Generally, bone resorption is enhanced in osteoporosis compared to bone formation, irrespective of the cause. 7 Bone mass that is −1 to −2.5 standard deviations relative to the peak bone mass of a healthy young adult radiographically is considered osteopenia, whereas osteoporosis is more than −2.5 standard deviations. 3 The decreased bone mass in osteoporosis predisposes to loss of height due to vertebral fractures. 3 Furthermore, vitamin D deficiency in the patient could increase parathyroid hormone (PTH) release (the major regulator of calcium homeostasis), increasing bone resorption, precipitously affecting an osteoporotic state. 4 Since the patient previously used bisphosphonates, a treatment that inhibits bone resorption, it is plausible that she may have severe osteopenia, which predisposed her to conditions described in the past medical history and observed on PE.

Which factors predispose to falls in the elderly?

Many factors predispose to falls in the elderly. Injury secondary to falls in the elderly is common, but the normal aging process does not precipitate falls independently. 8 Falling is considered a “geriatric syndrome." 9 Each year, 30%–40% of individuals over the age of >65 years fall a minimum of one time. 10 Falls account for approximately two-thirds of accidental deaths in individuals ≥65 years. 11 There is a two- to six-fold increase in future risk of falls associated with previous falls. 8 Hip fracture from a fall increases the likelihood the individual will be placed in a nursing home, which increases the risk of fall roughly three times compared to living in the community. 8 However, the patient denies any history of falls. Some other risk factors for falls include dementia, low muscle strength, poor vision, polypharmacy, resting tachycardia, and difficulty rising out of a chair. 12 Other cardiovascular, pulmonary and central nervous system disorders are also considerations.

Which factors may have predisposed to possible fractures in the patient?

Metastasis to the bone may predispose to pathologic fracture. 13 Pathologic fracture is a weakness of the bone structure rendering it incapable of resisting everyday biomechanical forces that generally do not cause a fracture. For example, a fall from bed should typically not cause a hip fracture. Multiple myeloma may cause lytic (bone resorbing), “punched out,” radiographic lesions of the pelvis, femur, and vertebral column. 13 Weight loss occurs in approximately one-quarter of patients with multiple myeloma, of which the patient's history does not report. 14

Furthermore, metastatic tumors involving the skeleton are the most common bone tumors in adults and may predispose to pathologic fracture. 3 Approximately 75% of bone metastases spread from the prostate, breast, kidney, and lung; skeletal metastases are usually multi-focal, involving the axial skeleton. 3 Metastatic skeletal lesions may be lytic radiographically, such as those from the kidney, lung, and gastrointestinal tract. 3 Prostate cancer metastasis generally produces blastic (bone-forming) skeletal lesions, but other types of cancers may cause blastic or mixed (blastic and lytic) skeletal lesions. 3 Conventional radiographs of the patient's hip and lumbosacral spine will help prioritize the differential based on if lytic or blastic lesions are present or generalized severe osteopenia is evident.

Other factors that may predispose to pathologic fractures include osteoporosis, which is the cause of a fracture every 3 seconds for someone worldwide. 15 The hip and spine are distinct fracture locations for patients with osteoporosis. 15 Several national osteoporosis guidelines utilize the Fracture Risk Assessment Tool (FRAX) algorithm, accessible to physicians in the primary care setting. 12 , 16

Which laboratory and imaging tests should be obtained for preadmission workup for suspected hip fracture? Discuss which other imaging studies should be obtained for the patient. Which laboratory tests should be obtained and what results are expected as evidence for osteomalacia?

The clinician should order a chest X-ray (CXR), urinary analysis (UA), complete blood count (CBC), coagulation panel, and electrocardiogram (ECG) as part of the preadmission workup. Conventional radiographs of the hip and lumbosacral spine should also be obtained based on the patient's PE. Since vitamin D deficiency may cause osteomalacia, laboratory results should be obtained, including vitamin D, calcium, phosphate, PTH, and alkaline phosphatase (ALP). An elevated level of ALP enzyme suggests bone disease (or liver disease). Low serum calcium, phosphate, 25-hydroxyvitamin D, and elevated PTH and ALP support osteomalacia. In contrast, these laboratory results should be normal in postmenopausal osteoporosis.

Diagnostic findings, Part 2

The patient's CXR demonstrates cardiomegaly without evidence of pneumonia, pneumothorax, or pleural effusion. UA, CBC, and coagulation panel results are summarized in Table 1 , Table 2 , Table 3 , respectively. Her ECG demonstrates tachycardia, a single P wave preceding each QRS complex, and T waves. Table 4 summarizes the laboratory results for vitamin D, calcium, phosphorus, PTH, and ALP enzyme.

Table 1

Urinalysis laboratory results.

Table 2

Complete blood count laboratory results.

Table 3

Coagulation profile.

Table 4

Serum calcium, phosphorus, parathyroid hormone vitamin D, and alkaline phosphatase laboratory results.

Conventional radiographs of the hips and lumbar spine are depicted in Fig. 1 and Fig. 2 , respectively.

Hip radiograph: Conventional AP radiograph of the hip demonstrates a comminuted displaced left intertrochanteric femur fracture (arrow) with foreshortening and mild medial angulation, with T-score of −3.9 on subsequent dual-energy X-ray absorptiometry.

Lumbar spine radiograph: Conventional lateral radiograph of the lumbar spine demonstrates multiple vertebral body compression fractures visualized on a background of diffuse osseous demineralization to include a severe compression fracture (>40% height loss) at L3 (arrow).

Questions/discussion points, Part 2

Interpret the patient's laboratory results, ecg, and imaging findings. what should be d o ne next based on the imaging findings.

The laboratory results are normal, indicating that no further workup is necessary for potentially admitting the patient to the hospital. Moreover, the normal ECG aligns with the patient's history and supports a non-cardiac etiology as the cause of her fall, such as syncope potentially caused by atrial fibrillation (irregularly irregular rhythm with absent P waves). The imaging, however, demonstrates hip fracture and multiple spinal compression fractures. Figure 1 is a conventional anteroposterior (AP) radiograph of the hip that demonstrates a comminuted displaced left intertrochanteric femur fracture (arrow) with foreshortening and mild medial angulation, with a T-score of −3.9 (bone mineral density (BMD), <3.9 standard deviations from the peak BMD in the healthy young adult) on subsequent dual-energy X-ray absorptiometry (DEXA). Figure 2 is a lateral lumbar spine conventional radiograph that demonstrates multiple vertebral body compression fractures visualized on a background of diffuse osseous demineralization to include a severe compression fracture (>40% height loss) at L3 (arrow).

Based on the DEXA scan T-score of −3.9 and normal serum levels of vitamin D, calcium, phosphorus, PTH, and ALP, osteoporosis with secondary hip fracture is prioritized on the differential. Cancer with pathologic fracture of the hip or metastases to the spine is far less likely based on the laboratory results and imaging. The next step is orthopedic consultation for the hospital admission. 17 Fracture dislocations of the femoral head are an orthopedic emergency. 17 Stable vertebral wedge compression fractures without neurologic deficits may be managed as an outpatient. 17 The patient's neurologic examination is normal; therefore, our acute chief concern is managing her hip fracture.

Which orders should be placed upon admission of the patient to the hospital?

Admission orders include non-weight bearing bedrest, foley catheter, nothing per oral (NPO) after midnight, and DVT prophylaxis.

What is this patient's overarching diagnosis?

The overall clinical picture for the patient is osteoporosis. The diagnosis of osteoporosis usually occurs after a fracture. 18 Osteoporosis is diagnosed by DEXA radiography, which determines BMD. 19 The World Health Organization (WHO) has specific diagnostic criteria for osteoporosis in postmenopausal women >50 years (but not for premenopausal women), which are spinal or hip T-score ≤ −2.5; normal BMD is within one SD of the young adult female reference. 19 To diagnose severe established osteoporosis, the criteria are BMD ≥2.5 SDs below the young adult female reference range and one or more fragility fractures. 19 One typical clinical sign reported by an individual with osteoporosis may be loss of height. 20 The patient's history and PE findings are consistent with osteoporosis based on DEXA score, history of bisphosphonate use, kyphoscoliosis, and hip fracture from a fall out of bed.

Discuss primary versus secondary osteoporosis. Which type of osteoporosis does the patient have?

There are two forms of osteoporosis: primary, the most common, and secondary. Primary osteoporosis refers to a precipitous loss of bone mass usually due to hypogonadism and increased age in the absence of recognizable chronic conditions predisposing to bone loss, primarily affecting individuals from 51 to 65 years. 19 Primary osteoporosis is further classified as types I and II. 18 Type I osteoporosis, postmenopausal osteoporosis affects females six times more than males; however, this type is seen in most individuals >70 years. 18 Type I osteoporosis is due to decreased estrogen (hypogonadism), primarily affecting postmenopausal women, and type II osteoporosis, senile osteoporosis, occurs twice as often in females than males and is primarily due to aging. 18 Deficiency in calcium, decreased vitamin D, and elevated PTH, which occur due to aging, help designate an individual with primary type II senile osteoporosis. 18 Primary osteoporosis may also occur in younger females who are status post-oophorectomy. 21 In contrast, secondary osteoporosis is due to established conditions that include celiac disease, cystic fibrosis, Crohn's disease, hypercortisolism, myeloma, HIV, rheumatoid arthritis, and medications. 22 While this list of conditions is not exhaustive, secondary osteoporosis generally occurs due to chronic conditions that affect bone mass, and therefore, may affect younger individuals. 23 Based on the patient's past medical history and laboratory results, she has primary type I osteoporosis.

Calculate this patient's FRAX score using the previously provided BMD for her left femur using an online tool. Explain when the FRAX score should be obtained. Discuss some of the limitations of the FRAX score.

The FRAX tool is used to calculate an individual's ten-year osteoporotic fracture and hip fracture risk. The FRAX probability of fracture is calculated based on age, sex, weight, height, prior fracture, fractured hip in parent, smoking, glucocorticoid use, rheumatoid arthritis, secondary osteoporosis, alcohol consumption, and femoral neck BMD. 16 The FRAX score for the patient indicates a major osteoporotic ten-year fracture risk of 45% and hip fracture risk of 24%. 16 The BMD of the femoral neck should be obtained for females 65 years or older. The FRAX algorithm requires answering if the individual has secondary osteoporosis based on whether the individual has type I insulin-dependent diabetes mellitus (DM), osteogenesis imperfecta, untreated chronic hyperthyroidism, premature menopause (<45 years), chronic malnutrition, and chronic liver disease. 16 A possible reason to help explain why type I DM is listed for the FRAX score calculation and not type II DM is because the former is associated with a reduced BMD, whereas the latter demonstrates normal or even increased BMD but diminished bone quality. 24 Therefore, type I DM predisposes to fracture based on a diminished BMD, which is why type I DM is included in the FRAX score calculation. Limitations of the FRAX score include underpredicting the risk of fractures in patients with recent fractures and individuals at increased fall risk. 6 The FRAX score is not intended for use in people <50 years or those treated for osteoporosis previously. 6 Surmise to say that the patient had previous vertebral fractures causing loss of height and kyphoscoliosis, presumably due to postmenopausal osteoporosis, and was treated with bisphosphonates.

Discuss treatment options for individuals with osteoporosis. What is a drug holiday?

Bisphosphonates are the first-line treatment for patients with osteoporosis. 25 The mechanism of action of bisphosphonates is to inhibit osteoclast activity. 25 Bisphosphonates are inorganic pyrophosphate analogs that integrate within the hydroxyapatite of bone. 25 Endocytosis of bisphosphonates by osteoclasts leads to their apoptosis. 6 The accumulation of bisphosphonates within bone after one year of use is what gives an individual added anti-fracture protection after stopping therapy. 25 Therefore, patients at low to moderate fracture risk may be advised to undergo a drug holiday, stopping treatment for two to three years after three to five years of taking bisphosphonates. 25 Recommendations for high-risk patients (previous osteoporotic fracture or risk for multiple fractures) are to continue taking bisphosphonates or switch to another osteoporosis medication, such as denosumab. 25 Denosumab is a monoclonal antibody that binds to the receptor activator of nuclear factor kappa B ligand (RANKL). 19 RANKL interacts with its receptor on osteoclasts normally, which increases their activity. Therefore, denosumab inhibits osteoclast activity and bone resorption.

Discuss restrictive lung disease due to kyphoscoliosis in the patient in terms of the pathogenesis

Due to osteoporosis, vertebral compression fractures in the thoracic spine may lead to kyphoscoliosis. 3 , 26 Chest wall deformity resulting from kyphoscoliosis is one cause of restrictive lung disease, which likely explains the patient's difficulty breathing since her CXR is otherwise clear. 27 Balancing pain control and respiratory effort are a consideration when deciding if I-M morphine should be administered due to its potential for acute respiratory depression.

Diagnostic findings, Part 3

A section of vertebrae obtained at autopsy from a patient with a severe form of osteoporosis is shown in Fig. 3 . Histology of affected bone is shown in Fig. 4 and Fig. 5 A, with comparison to non-osteoporotic bone as shown in Fig. 5 B.

Gross photo of vertebrae with severe osteoporosis. Notice the wide spacing between the very thin trabeculae. The cortex is barely visible. The height of the vertebral bodies is markedly diminished. The middle vertebral body shows a compression fracture (arrows). The weakened vertebral body collapses under the pressure of the body's weight.

This bone section demonstrates marked thinning of the cortex (arrowhead) and trabeculae. Trabecular interconnections are significantly diminished. (H&E, low-power magnification).

(A) Mild osteoporosis. This section of femoral bone shows decreased trabecular thickness and trabecular interconnections compared to non-osteoporotic bone (B). (H&E, both images at 20X).

Questions/discussion points, Part 3

Describe the gross and histologic findings as shown in fig. 3 , fig. 4 , fig. 5 . compare the histology of osteoporotic to non-osteoporotic bone.

Figure 3 demonstrates the diminished thickness of the vertebral bodies and a compression fracture of the middle vertebral body. There is space widening between the markedly thin trabeculae, and the cortex is inconspicuous. On histology, a low-power view shows a thinned cortex and trabeculae and a lack of trabecular interconnections ( Fig. 4 , Fig. 5 ). Compared to a healthy person, bone from individuals with osteoporosis demonstrates changes in the trabecular compartment. 28 The trabecular bone in osteoporosis has a heterogenous bone density and microarchitecture. 28 This is especially true of the vertebrae and proximal femur. 28

How are patients typically diagnosed with osteoporosis?

Bone biopsy in patients with osteoporosis is rarely performed due to its invasiveness, lack of clinician's technical training to perform the biopsy, pain, cost, few centers available to analyze the bone collection, delays between biopsy and completion of the pathology report, and a gap in knowledge regarding the meaning of the morphological results. 5 In the context of vertebral compression fractures, a bone biopsy is not often utilized but may uncover malignancies (metastasis or multiple myeloma) with otherwise normal laboratory results. 29 DEXA assessment is the gold standard clinicians rely upon to diagnose osteoporosis. 19 The Choosing Wisely initiative recommends DEXA to screen for osteoporosis in women with no other risk factors beginning at 65 years and offer other essential information for the clinician. 19 , 30

Discuss the stages of bone healing

There is a loss of the otherwise contiguous bone structure in a fracture. 7 Fracture healing has three phases: (1) inflammatory, (2) reparative, and (3) remodeling. 7 Age, fracture location, the patient's overall health, nutrition, and extent of injury affect fracture repair. 7 Fracture repair involves intramembranous ossification (stabilized fracture) or endochondral ossification (non-stabilized) fracture. 31 As many as, 10%–15% of the 15 million fractures each year end up with incomplete healing. 31 In osteoporosis, there is a prolonged fracture healing time and impairment in subsequent healing outcomes with decreased BMD and biomechanical properties. 31

The cells and processes involved in earlier bone development and remodeling also facilitate fracture repair. 32 The inflammatory phase involves hematoma formation due to torn blood vessels and the release of clotting factors 32 within two to five days after fracture. 7 In the reparative phase, a fibrocartilaginous mass is formed, known as a pro-callus. 32 Woven bone eventually replaces the pro-callus, forming a hard callus. 32 A microfracture with callus formation is demonstrated on bone histology ( Fig. 6 ). Woven bone appears within seven days in fracture repair. 7 However, woven bone has a haphazard arrangement of collagen type 1 fibers, hence the name woven. 3 Although this provides initial structural support, maximum strength is achieved through remodeling as lamellar compact or cancellous bone. 3 In adults, any woven bone is abnormal. 3 In the remodeling phase, the bone cortex becomes again contiguous with the non-fractured sites, and a functional blood supply is restored. 7 , 32

A microfracture with hard callus formation is demonstrated in this bone section in a patient with significant osteoporosis. (H&E, intermediate power magnification).

Discuss the quality of life after hip fracture in the elderly

Hip fracture is the leading injury diagnosis for admission of the elderly to the hospital. 33 Some estimates are that hip fracture is the cause of mortality in 25% of elderly patients one year after injury. 33 Self-care, ambulation, and mobility are diminished following hip fracture. 34 The reduction in an individual's quality of life after a hip fracture continues for many years. 34

Teaching points

• • Osteoporosis is a metabolic bone disease in which skeletal mass is histologically normal but reduced, and bone resorption always exceeds formation.
• • Osteopenia and fractures of the hip and spine are hallmarks of all types of osteoporosis.
• • The normal mineralized to non-mineralized bone ratio is always unaffected by osteoporosis disease progression.
• • Risk factors for falls in the elderly include dementia, low muscle strength, poor vision, polypharmacy, resting tachycardia, and difficulty rising out of a chair.
• • Risk factors for fracture are low body mass index, previous fracture (vertebral fracture), parent fractured hip, current smoking, glucocorticoids, rheumatoid arthritis, secondary osteoporosis, and alcohol three or more drinks daily.
• • The FRAX tool can be used to calculate an individual's ten-year osteoporotic fracture and hip fracture risk.
• • Primary osteoporosis, the most common form of osteoporosis, typically affects postmenopausal women, whereas secondary osteoporosis is due to an underlying disease, medication, or alcohol use.
• • Primary osteoporosis is divided into types I and II. Type I osteoporosis, postmenopausal osteoporosis, is related to hypogonadism or estrogen deficiency, whereas type II osteoporosis, senile osteoporosis, is primarily due to aging, and therefore, may be related to a deficiency in calcium, decreased vitamin D, and elevated PTH, which laboratory results may support.
• • The WHO diagnostic criteria for osteoporosis in postmenopausal women >50 years are spinal or hip BMD ≥2.5 SDs below the reference mean for the young adult female (T-score ≤ −2.5).
• • Bisphosphonates are inorganic pyrophosphate analogs that chelate to bone and work by inhibiting osteoclasts.
• • Kyphoscoliosis secondary to osteoporosis is a cause of restrictive lung disease.
• • Bone fracture repair has three phases: (1) inflammatory, (2) reparative, and (3) remodeling.
• • Osteoporosis demonstrates delayed fracture healing and reduces mechanical properties.

Author's note

Fig. 3 , Fig. 4 , Fig. 5 , Fig. 6 were obtained during the scope of US government employment for Dr. Conran.

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of competing interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of the article.