Study of secondary causes of male osteoporosis

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1 Study of secondary causes of male osteoporosis Suárez, S.M., Giunta J., Meneses G., Costanzo P.R., Knoblovits P. Department of Endocrinology, Metabolism and Nuclear Medicine of Hospital Italiano of Buenos Aires, Argentina Male osteoporosis (OP) is an underdiagnosed and undertreated disease in the majority of men. One third of hip fractures occur in men, who present more secondary complications than women, with a mortality rate of 37.5% within one year of fracture. The observation that most fractures occur in men, whose bone mineral density is not in the osteoporotic range, highlights the importance of different factors other than bone densitometry to evaluate the risk of fracture. Aims: to establish the prevalence of secondary factors OP in men older than 50 years and to analyze the possible associations between bone mineral density and biochemical parameters. Retrospective analysis of 918 medical records of men over 50 years old, admitted because of OP, osteopenia or bone fractures in any site. Inclusion criteria: measurements of plasma and urinary bone metabolism, total testosterone, lumbar spine, femoral neck and trochanter bone densitometry parameters. Results: 113 patients met the inclusion criteria, the mean age was 70.6 ± 9.8 years, of which 85 (75.2%) had OP diagnosis in one site and 28 (24.8%) osteopenia. Of 113 patients assessed, 97 (85.8%) had secondary OP causes, such as hypovitaminosis D, hypogonadism, chronic corticotherapy and hypercalciuria. Twenty two per cent of the patients had suffered a fracture without previous suspicion of low bone mass. Conclusions: A high proportion of men with OP present secondary factors. Most of these factors are diagnosed by history taking and biochemical study. The diagnosis of male OP is delayed, as 22% had suffered a fracture without previous suspicion of low bone mass. This indicates the importance of this issue and its early diagnosis and treatment in the male population. No financial conflicts of interest exist. Key words: Male osteoporosis; Hypovitaminosis D; Secondary causes; Bone fracture INTRODUCTION Osteoporosis (OP) is a metabolic bone disease characterized by low bone mass and microarchitectural deterioration, leading to increased bone fragility and subsequently increased fracture risk. (1) At present, male osteoporosis is hardly investigated, underdiagnosed and, therefore, undertreated (2). There was a higher prevalence of secondary causes of OP in men than in women. The annual loss of bone mineral density (BMD) in men is around 1% and we estimate that 7% of white men, 5% of black men and 3% of Hispanic men suffer from OP (3-5). The fracture incidence in male population has a bimodal distribution curve with adolescence and elderly age being the two stages in life when the highest number of bone events occur (6-7). Regarding the importance of this issue, one out of eight men over 50 years old is going to develop OP-related fractures (8). The annual worldwide incidence of fractures is estimated at about 9 million, 39% of which occur in men (9), and a continuous increase is expected in the number of hip fractures in the next few years, mainly among men (10). In our country, a study performed in 2005 in the city of Rosario shows that the incidence of hip fractures during in the population studied was 290 every 100,000 inhabitants (405 women and 137 men), with men being younger than women at the time of fracture (11).

2 The purpose of this study was to establish the prevalence of OP secondary causes in men over 50 years old and to analyze the potential relationships between BMD and different biochemical parameters. MATERIAL AND METHODS We retrospectively evaluated 918 medical records (from our electronic file of ITALICA medical records) of men over 50 years old whose reason for admission or medical history was: OP, osteopenia or bone fracture, whatever its site. We obtained personal history data related to cigarette smoking, alcohol consumption, physical activity, age, weight, prior corticosteroid therapies, anti-androgens and family history of osteoporosis or fractures. 1 Laboratory: We only considered the medical records of patients with measurements of the following serum and urinary parameters: - Total serum calcium, serum creatinine and total serum testosterone (Total To) hour uurine calcium and creatinine. Other laboratory measurements were also considered although the medical records of patients without such measurements were not excluded: parathormone (PTH), 25 (OH) Vitamin D (25OHD) and antibodies for celiac disease diagnosis. Calcium and creatinine measurements were performed using standardized automated laboratory methods. Plasma calcium: indirect ISE (normal: mg/dl); 24-hour urine calcium: calculated method; plasma creatinine: Jaffe kinetic method (normal: mg/dl); 24-hour urine creatinine: calculated method; intact PTH: Siemens IMMULITE Chemiluminescence, (normal: pg/ml); 25OHD: RIA DiaSorín (normal: ng/ml) and Total To: Siemens IMMULITE Chemiluminescence (normal: ng/ml). To diagnose hypercalciuria, the urine calcium/creatinine ratio in 24-hour sample should be 0.31 mg/mg. Hypovitaminosis D was defined by 25OHD levels 30 ng/ml. Below such levels, we noticed an increase in PTH values and in bone resorption markers according to Mc Kenna and Freaney classification (12). 2 Bone Densitometry: Bone Mineral Density (BMD) was measured by dual energy x-ray absortiometry (DXA) using a LUNAR Prodigy densitometer. We considered absolute values (g/cm 2 ) and BMD T-score in lumbar spine (LS), femoral neck (FN), trochanter (T) and total hip (TH). Of the total number of patients studied, 113 met the inclusion criteria. All studies were performed in our institution. Statistical analysis: Instat Statistical Software (GraphPad, version 3.01), t test for unpaired samples, Chi Square and Pearson correlation. Data are presented as X±SD. A p<0.05 value was considered significant.

3 RESULTS We included 113 patients of 70.6 ± 9.8 years, 75.4 ± 11.7 kg and body mass index (BMI) of 26.9 ± 3.5 kg/m 2. Of the total number of patients, 85 (75.2%) had been diagnosed with OP in at least one site (79 received subsequent treatment with bisphosphonates and 2 with strontium ranelate) and 28 patients (24.8%) had osteopenia. 24.8% (n=28) of patients suffered at least one bone fracture (23 patients with OP and 5 with osteopenia). 22.1% (n=25) suffered a fracture before being diagnosed with low bone mass (21 patients with OP and 4 with osteopenia). Fracture sites were: 8% hip fracture, 64% vertebral fracture and 28% in other sites (Figure 1). The age at the time of the fracture was 66.7 ± 10.6 years. No significant differences were found in the BMI of patients with prior fracture and not fractured patients: 27.7 ± 3.8 versus 26.8 ± 4.1 kg/m 2, respectively. (References: Fracturas vertebrales = vertebral fractures; Fracturas de cadera = hip fractures; Otras localizaciones = other sites) Figure 1. Types of fracture in patients without previous diagnosis of low bone mass (n=25). In 85.8% (n=97) of patients a low bone mass or fracture secondary cause could be determined. Of the total number of patients studied, 23.9% (n=27) were smokers. 15.9% (n=18) had a family history of OP or fractures. Three patients (2.6%) had low weight (BMI < 20 kg/m 2 ), while 5 (4.4%) had lost over 10% of their weight the year before being diagnosed. 20 out of 110 patients (18.2%) were being treated with chronic oral and parenteral corticosteroids and 4 patients (3.5%) were being treated with luteineizing hormone releasing hormone (LHRH) analogs and anti-androgens for prostate cancer. 19.5% (n=22) of patients had hypercalciuria in at least two successive evaluations; we could not establish if the cause of hypercalciuria was a high bone turnover or renal tubulopathy since we did not measurements of bone resorption markers or the evaluation of the urine calcium/creatinine ratio in 2-hour samples. Low total To was found in 25.4% of patients (Total To < 2.8 ng/ml), without including 4 patients with hormone blockage. The presence of antibodies that are markers of celiac disease was evaluated in 37 patients, with the test being positive in 2 of them (Figure 2).

4 (References: Hipogonadismo = Hypogonadism; Tabaquismo = Cigarette Smoking; Hipercalciuria = Hypercalciuria; Historia familiar de OP o fracturas = Family history of OP or fractures; Pérdida > 10% del peso corporal = Loss > 10% of body weight; Análogos LHRH = LHRH analogs; Bajo peso = Low weight; Causas secundarias de baja masa ósea = Secondary causes of low bone mass; % de pacientes = Patients %) Figure 2. Secondary causes of low bone mass (n=113). OP: Osteoporosis; LHRH: luteineizing hormone releasing hormone. Figure 3. Levels of 25 (OH) Vitamin D (n=79) 25OHD was measured in 79 patients, 62% had hypovitaminosis D (Figure 3). We noticed a positive correlation between the 25OHD level and BMD of FN (r=0.28), p=0.01) Figure 4; 25OHD and BMD of TH (r=0.36, p=0.008) (Figure 5) and 25OHD and BMD of T (r=0.39, p=0.001) Figure 6. There was no correlation between the levels of 25OHD and BMD of LS. Within the group of patients where vitamin D was measured, smokers (n=18) had lower levels of 25OHD compared to non-smokers (n=49): 20.0 ± 8.1 vs ± 11.7 ng/ml, p=0.033, respectively.

5 PTH was measured in 67 patients: primary hyperparathyroidism was found in 5 (7.4%) and secondary hyperparathyroidism in 31 (46.2%). No correlation was found between PTH and BMD of LS, FN, T or TH. There was no correlation between Total To and calciuria levels with BMD values of LS, FN, T or TH. There were no differences between fractured and not fractured patients when comparing the levels of 25OHD, PTH, Total To, 24-hour urine calcium, 24-hour urine calcium/creatinine, age and BMD of LS, FN, T or TH. Figure 4. Correlation between 25OHD and BMD of FN (r=0.28, p=0.01). 25OHD: 25 (OH) Vitamin D; BMD: Bone Mineral Density; FN: Femoral Neck. Figure 5. Correlation between 25OHD and BMD of TH (r=0.36, p=0.008). 25OHD: 25 (OH) vitamin D; BMD: Bone Mineral Density; TH: Total hip.

6 Figure 6. Correlation between 25HOD and BMD of T (r=0.39, p=0.001). 25OHD: 25 (OH) vitamin D; BMD: Bone mineral density; T: Trochanter. Figure 7. Correlation between the number of risk factors and BMD of LS (n=113) (r=0.32; p=0.0015). BMD: Bone mineral density; LS: Lumbar spine

7 Figure 8. Correlation between the number of risk factors and BMD of LS in patients with prior fracture (n=25) (r=0.52; p=0.017), BMD: Bone mineral density; LS: Lumbar spine Based upon the study carried out by Koshla et al. (6), where different risk factors for OP were suggested, we correlated the factors that could be evaluated in this retrospective study (cigarette smoking, hypercalciuria, sedentary lifestyle, chronic corticosteroid therapy, hypogonadism, hyperparathyroidism and anticonvulsant drugs) with the BMD values of patients. We noticed a negative correlation between the number of risk factors and BMD in LS (r=0.32; p=0.0015) Figure 7. There was no correlation between the number of risk factors and BMD in FN, T or TH. When evaluating the subgroup of patients with prior fracture, we found the same negative correlation between the number of risk factors and BMD of LS (r=0.52; p=0.017) (Figure 8). DISCUSSION The diagnosis of male OP is mainly based upon BMD measurement and it is determined when the T-score value is < This definition relies on the standards used to define female OP and are likewise considered suitable for men. At present, there are no standards to define male OP. Taking into account the research studies on OP published between 2000 and 2005, 77% correspond to women and only 23% to men (man to woman ratio 1:3.6). The prevalence of osteopenia in women over 50 years old is estimated at 43% and in men over 50 years old in 37% (man to woman ratio 1:1.6); the prevalence of OP in women over 50 years old is estimated at 16% and in men over 50 years old, 6% (man to woman ratio 1:2.6) (13). There is no linear relationship between the number of studies focused on male OP or osteopenia and the rate of these conditions. Male OP is a hardly studied and therefore, underdiagnosed disease. The annual incidence of hip fracture in persons over 65 years old is 8-10/1000 women and 4-5/1000 men (man to woman ratio 1:2) (14). Men have a higher risk of fractures in any site after low trauma fractures compared to women (15). The mortality rate associated to vertebral or hip fracture is higher in men than in women, being twice particularly in the case of hip (16-20). Different studies show that mortality risk in men one year after a hip fracture ranges between 30 and 35%, while in women, such rate would be between 15 and 20% (21-23).

8 Men are rarely treated with anti-resorptive drugs after fractures (24-25), so we can assume that male OP is undertreated. A 5-year follow-up study of 110 men between 53 and 99 years old admitted with atraumatic hip fracture showed that 43% had 5 or more medical records that could influence on BMD and only 5 of them (4.5%) had received OP treatment upon being discharged from hospital. During the follow-up period, 27% of such population received some kind of OP treatment; 67% only received calcium and vitamin D (24). Of the total number of patients with OP evaluated in our study, 95% received bisphosphonate therapy following diagnosis. Of the group of patients with osteopenia, 43% were treated with anti-resorptive drugs (all of them with at least one risk factor for fractures and 3 of them with a prior fracture history). OP secondary factors are common to both sexes, however, it is more frequent to find them in men. Epidemiologic studies show that they can be identified in 40-60% of men that suffered a fracture and within the most prevalent ones we can find: hypogonadism, poor absorption syndromes, chronic glucocorticoid use, hypovitaminosis D, hypercalciuria, cigarette smoking and alcoholism (26-29). When evaluated as a whole, these risk factors are strong predictors of low bone mass and hip fracture, even without densitometry evaluation (30-31). However, they were not useful to predict the response to medical treatment (32). In the male population included in our study, we found that hypogonadism, cigarette smoking, hypercalciuria and chronic corticoid therapy were the main secondary reasons for low bone mass and although not evaluated in all patients, hypovitaminosis D would be another major factor in the deterioration of bone mineral density. The most common cause of secondary osteoporosis is chronic corticoid therapy, a situation that is reversible upon discontinuation of drugs (33). Between 30 and 50% of patients under corticoid treatment have a higher risk of mainly hip or spine fracture (34-35). As with smokers, the higher the exposure time and dose, the higher the deleterious effects at bone level (36). Both androgens and estrogens have an effect at bone level (37). Several studies show a higher risk of non-vertebral and hip fracture with lower bioavailable estradiol values(e2). Likewise, there was a positive correlation between hip BMD and bioavailable E2 levels. However, there is no clear association between risk of fracture and BMD with total To and bioavailable To values (38). In this study, we did not find any association between total To and BMD values of LS, FN, T or TH, a result consistent with the information previously stated. Regarding cigarette smoking, since a long time ago, it has been recognized as a major risk factor for lower bone mass and higher risk of fractures (39). Smoking has proved to be an independent risk factor for lower BMD in femoral neck and spine both in men and women (40). Particularly among men, it has been demonstrated that smokers have approximately 7% less bone mineral density in lumbar spine compared to nonsmokers (41), and that there is a direct relationship between the time and number of cigarettes smoked and the risk of fracture, which has been estimated in a 10 to 30% increase per decade (42). It is not clear how tobacco affects bone and several mechanisms have been suggested. Kanis study shows that only 23% of the increased risk of fractures in smokers was due to lower BMD, thus suggesting that other extraskeletal effects should be considered (43). Men who smoke have lower muscle mass index and higher appetite suppression (44-45). Other possible effects are through the alteration of E2 plasma values by either the conversion to an inactive metabolite or aromatase inhibitors (44-45). Finally, cigarette smoking would also have a negative effect on the plasma values of vitamin D (48). In our study, we found lower 25OHD levels in smokers. Another factor associated with lower bone mass is hypovitaminosis D. Vitamin D is one of the main hormones that regulate bone mineralization and homeostasis of calcium,

9 phosphorus and magnesium through proper bowel absorption of calcium and phosphorus; bone formation, resorption and mineralization and maintenance of neuromuscular function. Our study showed that over half of the patients with 25OHD measurements, had values below 30 ng/ml. At those levels, PTH starts to increase with higher risk of secondary hyperparathyroidism, increase in bone resorption and higher risk of fracture (49). Ensrud et al evaluated 25OHD values in men over 65 years old and found that with 25OHD below 20 ng/ml, there is a higher loss of bone mass at hip level (50). In a study of 1319 patients, 643 of which were men of 75.7 ± 6.6 years old, there was a positive correlation between 25OHD and BMD at total hip and trochanter level (51). In the population studied, we found a positive correlation between 25OHD values and BMD of FN, T and TH. It is well known that bone densitometry is the standard method to diagnose OP (52). Patients with T-score < -2.5 have a higher relative risk of fracture, which about doubles for each SD reduction in BMD (53). But there is a higher number of fractures in patients with T-score > -2.5 since there is a significantly larger number of individuals in this group. Therefore, the detection of other risk factors, different from T-score, that may increase the incidence of fractures, supplements diagnosis and contributes to the adoption of proper therapeutic measures, thus increasing sensitivity and specificity in the evaluation of the patient s bone risk (54-55) In our population, we could determine that the total number of patients fractured was 28. Five of them had osteopenia at a certain site (equivalent to 18% of the total number of patients in this group), and 23 osteoporosis (82% of the total number of patients in this group). It should be noted that around 22% of subjects evaluated had suffered a low impact fracture before being diagnosed with OP or osteopenia. In these cases, patient s diagnosis and treatment were late thus increasing morbidity and mortality rates and the risk of suffering new fractures in the future. Several tools have used throughout time to evaluate the risk of suffering an OP-related fracture, but most of them either unspecific or have not been validated in other populations (56-59). In 2008, the World Health Organization, proposed the FRAX (Fracture Risk Assessment Tool) that estimates a 10 years probability of suffering hip or combined fracture in untreated patients, based upon the presence of risk factors in addition (or not) to the information provided by bone densitometry. Although such tool has been validated in large populations, most patients studied were women, therefore, one of its limitations is its validity in males ( 60-61). We can conclude that male OP is an underdiagnosed and undertreated disease. The occurrence of fractures is frequent in men with low bone mass and results in a significant increase in morbidity, mortality (even higher than in women), and disability rates with the resulting impact on both individual economy and public health. Male OP is frequently associated with secondary causes, being the most frequent: hypogonadism, cigarette smoking, hypercalciuria, hypovitaminosis D and chronic corticosteroid use. Male fracture prevention should be a priority issue for public health. Since most fractures occur in men whose BMD is not within an osteoporotic range, it is important to find risk factors different from bone densitometry, and thus evaluate and eventually treat groups with a high risk of future bone fracture, not only with pharmacological treatment but also with favorable changes in their lifestyles. Anyway, the data collected in this retrospective study are not enough evidence to determine future approaches; therefore, it is necessary to conduct a prospective evaluation in our population about the prevalence of OP, osteopenia and risk factors to reach more accurate conclusions. These data emphasize the importance of developing proper guidelines for the detection and prevention of fractures associated with low bone mass in men.

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