Management of osteoporosis in men based Ukrainian version of FRAX

Objective. The aim of the study was to evaluate the impact of the previous published FRAX thresholds in a male referral cohort from Ukraine. Methods. The cohort comprised 653 men aged 40‒88 years (mean age 60.5 ± 11.8). The 10-year probabilities of hip fracture and a major osteoporotic fracture were calculated using the Ukrainian FRAX model. The intervention threshold was set at the age specific fracture probability as first used by the National Osteoporosis Guideline Group for FRAX-based guidelines in the UK and adapted for the Ukraine. Treat - ment pathways were compared with a previously published fe - male referral cohort from Ukraine. Results. 27 % of men and 51 % of women referred for skeletal assessment had a prior fracture that categorized eligibility for treatment that was more fre - quent in women than in men. The requirement for BMD testing was also higher in women than in men (18.3 % vs. 4.9 %, respectively). If referral for fracture risk assessment was contingent on the presence of at least one FRAX risk, the proportion of men and women eligible for treatment would rise from 5 % to 89 % in men and from

Objective. The aim of the study was to evaluate the impact of the previous published FRAX thresholds in a male referral cohort from Ukraine. Methods. The cohort comprised 653 men aged 40-88 years (mean age 60.5 ± 11.8). The 10-year probabilities of hip fracture and a major osteoporotic fracture were calculated using the Ukrainian FRAX model. The intervention threshold was set at the age specific fracture probability as first used by the National Osteoporosis Guideline Group for FRAXbased guidelines in the UK and adapted for the Ukraine. Treatment pathways were compared with a previously published female referral cohort from Ukraine. Results. 27 % of men and 51 % of women referred for skeletal assessment had a prior fracture that categorized eligibility for treatment that was more frequent in women than in men. The requirement for BMD testing was also higher in women than in men (18.3 % vs. 4.9 %, respectively). If referral for fracture risk assessment was contingent on the presence of at least one FRAX risk, the proportion of men and women eligible for treatment would rise from 5 % to 89 % in men and from 57 % to 93 % in women. Conclusions. This study demonstrated a higher need for both antiosteoporotic treatment without DХA and additional densitometric examination to further assess the osteoporotic fractures risk in Ukrainian women compared to men and the need for special attention in fracture risk assessment in men with previous fractures. The development of National guidelines together with a validation based on cost-effectiveness would help drive a cohesive national approach to risk assessment in both men and women.

Introduction
Osteoporosis and its complications are an important medical and social issue both in Ukraine and worldwide [1]. A recent study in 5 countries of the European Union indicated that the number of fractures will increase from 2.7 million in 2017 to 3.3 million in 2030 (by 23 %), and the annual costs associated with fractures (i. e. 37.5 billion euros in 2017) will increase by 27 % [2]. Osteoporosis affects women more frequently than men due to differences in the attainment of peak bone mass and in bone loss after menopause [3] and relatively few studies have focused on men. However, timely assessment of the risk of osteoporosis and its complication in both women and men is important in the prevention of this severe disease in an aging population.
The web-based tool FRAX ® (https://www.sheffield.ac.uk/FRAX) computes the 10-year probability of fragility fractures based on several common clinical risk factors and, optionally, a bone densitometry result obtained from dual energy X-ray absorptiometry (DXA) [4,5]. FRAX models are available for 73 countries covering more than 80 % of the world population at risk and have been incorporated into more than 100 guidelines worldwide [6].
A country specific FRAX model for Ukraine was launched in November 2016, replacing the Austrian FRAX model previously used [7,8]. Intervention thresholds for Ukraine have been published and tested in a female referral cohort from Ukraine [9]. The aim of the present study was to evaluate the impact of the published thresholds in a male referral cohort from Ukraine.

Population sample
The cohort comprised 653 men referred as outpatients to the Dmitry F. Chebotarev Institute of Gerontology of the National Academy of Medical Sciences of Ukraine for the evaluation of skeletal status. The study was approved by the local Ethics Committee (protocol № 5 of May 17, 2017) and undertaken from September 2017 to December 2020. All the study participants gave informed written consent for participation.
The baseline characteristics for the calculation of fracture probabilities are given in table 1. Complete information was available in all 653 patients. Bone mineral density (BMD) of the femoral neck was measured by DXA and the BMD was standardised according to the equipment manufacturer [10,11].
The T-score was calculated using the NHANES III reference values for young Caucasian women [10] as used in FRAX [12].

Fracture probabilities and management thresholds
The 10-year probabilities of hip fracture and a major osteoporotic fracture were calculated using the Ukrainian FRAX model (FRAX version 4.2). Calculations were undertaken with and without the inclusion of femoral neck BMD. Notes. BMI -body mass index, BMD -bone mineral density, Data presented in M ± SD and Range (Min-Max) or in % (n). The intervention threshold was set at the age specific fracture probability equivalent to women with a prior fragility fracture as first used by the National Osteoporosis Guideline Group for FRAXbased guidelines in the UK [12] and adapted for the Ukraine [8,9].

Management pathway
The management pathway explored was identical to that previously described in a female referral population. In brief, men with a prior fragility fracture were considered eligible for treatment. In those without a prior fracture, FRAX would be calculated without BMD. Fracture probability could thereafter be categorised as low, intermediate, or high (green, amber or red areas in figure). Patients categorised as low risk would not normally be given bone-specific intervention. Those at high risk would be eligible for treatment without necessarily having a BMD test (other than to provide a baseline to monitor treatment). Those at intermediate risk would be offered a BMD test and FRAX recomputed with the addition of BMD. Patients would then be re-categorized to low or high risk if the fracture probability fell below or above the intervention threshold, respectively.
Data derived for men were compared with that derived from a female referral population (3179 women, age 40-90 years) to the same institute [9].

Statistical Analysis
We performed the statistical analysis using Statistica 10.0 software. The relevance of sample in terms of the normal distribution principle was checked by Shapiro-Wilk's test and demonstrated abnormal distribution of FRAX parameters. The data were presented as n (%), mean values (M) and standard deviation (SD) or median (Me) and the lower and upper quartiles (25Q÷75Q) according to data distribution.

Results and their discussion
Probabilities of hip fracture and a major osteoporotic fracture (with and without BMD) are given in table 2. The mean probability of a major fracture was 3.8 % and, for a hip fracture was 1.3 % when BMD was used in the FRAX model (the same indexes without BMD consisted 3.1 and 0.8 %). Fracture probability calculated with BMD was higher than that without BMD. The probable reason for this is the preferential referral of men with lower-than-average BMD. Notes. MOF -10-year probability of major osteoporotic fractures, BMD -bone mineral density.  Notes. MOF -10-year probability of major osteoporotic fractures, HIP 10-year probability of hip fractures.

Management pathway
174 of 653 men (26.6 %) had a prior fragility fracture and would be eligible for treatment on this basis. At the initial assessment (FRAX without inclusion of BMD), no men were eligible for treatment. Of these, 447 low risk individuals (68.5 % of whole cohort, 93.3 % of males without previous fractures) would not normally be eligible for further assessment in that their fracture probability lay below the lower assessment threshold. The intermediate cate gory of risk comprised 32 men (4.9 % of whole cohort) in whom FRAX would be recalculated with the inclusion of femoral neck BMD. Of these 23 were categorized at low risk (3.5 %) and 9 at high risk (1.4 % of whole cohort). The overall disposition of the cohort is shown in table 3 and compared to that of women.
The disposition of the cohort in men was markedly different to that for women. Those eligible for treatment was 28 % of men and 57 % of women. For both sexes, eligibility was primarily determined by the presence of a prior fragility fracture but eligibility for treatment by FRAX alone was higher in women than in men (6.1 % vs. 1.4 % of whole cohort, respectively). The requirement for BMD testing was also higher in women than in men (18.3 % vs. 4.9 % of whole cohort, respectively). As might be expected, fracture probabilities were lower in men than in women (see table 3).
Not all men and women had a FRAX clinical risk factor. In the low-risk categories, 1442 of 1585 women and 349 of 470 men (n = 349; 53.4 % of whole cohort; 73 % of males without previous fractures) had no FRAX-based clinical risk factor. Thus, if referral for fracture risk assessment w as contingent on thepresence of at least one FRAX risk, the proportion of men and women eligible for treatment (amongst those with at least one FRAX risk factor) would rise from 5 % to 89 % in men and from 57 % to 93 % in women.
In a historical context, osteoporosis has been viewed as a disorder of women rather than men, and the majority of studies covering assessment and treatment have focused on women [1]. In recent years, it is increasingly recognized that osteoporosis and fragility fractures are also common in men. In 2019 there were estimated to be 32 million individuals in Europe with osteoporosis as defined by densitometry of whom 6.5 million (20 %) were men. In the same year, there were 4.2 million fragility fractures of which one third were in men [13]. Of 29 countries in Europe surveyed, all but four provided for men in guidelines for the assessment of osteoporosis.
According to the State Statistics Service of Ukraine data (01.01.2020 [14]) there were 19 343 440 men (46.4 % of the total population) and 10.17 % of males aged 50 years and older. According to the Ukrainian Research and Medical Center for Osteoporosis, 28.4 % of men in this age group have low BMD according to the DRA, and 6.7 % -osteoporosis. Thus, our calculations indicate that in Ukraine more than 123 thousand men aged 50 years and older have osteoporosis and almost 560 thousand -osteopenia.
The impact of fragility fracture is similar in men and women, in terms of fracture site, associated comorbidity and reduced survival [13,[15][16][17][18]. This raises the question of whether there are intrinsic differences between men and women, which impact on the assessment of fracture risk with the use of FRAX. In the case of clinical risk factors, no systematic sex differences have been observed in the strength of the clinical risk factors (apart from age) [4]. With regard to BMD, at any given age the average BMD is higher in men than in women. However, the gradient of risk (increase in fracture risk/SD decrease in BMD) is the same in men as in women [19]. Moreover, the absolute incidence of hip fracture and of all fractures by femoral neck T-score also appears similar in men and women [20,21]. These data support the view that FRAX can be applied equally to men as to women.
In the present study, we have examined the assessment of fracture risk in a referral population of men and compared their disposition with that of a referral population of women. Many men and women referred for skeletal assessment had a prior fracture that categorized eligibility for treatment, a characteristic that, as might be expected was more frequent in women (51 % of referrals) than in men (27 %). Of the remaining men, very few men were eligible for treatment under the current management pathway, principally because the majority of men with no prior fracture had no clinical risk factors. These findings suggest that referral for fracture risk assessment should be recommended in men with at least one clinical risk factor. Alternatively, intervention thresholds should be made less conservative. The various options might be optimally explored by health economic assessment.
Limitation. These findings are relevant for the referral population to the present institute and may not reflect practice elsewhere in the Ukraine. The development of National guidelines together with a validation based on cost-effectiveness would help drive a cohesive national approach to risk assessment in both men and women.

Conclusions
The fragility fracture was the most frequent (26.6 %) risk factor for osteoporotic fractures in Ukrainian males (the corresponding index in females was 51.3 %), and it was the reason for antiosteoporotic treatment initiating. Only 6.7 % of men without previous fractures were found to require additional DXA examination according to FRAX and none had a high fracture risk. 73 % of men without fractures did not have any risk factor included in the FRAX algorithm. This study showed a greater need for both antiosteoporotic treatment without DXA assessment and additional densitometric examination for the osteoporotic fracture risk assessment for the Ukrainian women rather than men, and necessity of special attention to the presence of previous fractures in males, and consideration of other osteoporosis risk factors which are not included in this FRAX.