Management of Osteoporosis in Men: A Narrative Review

Male osteoporosis is a still largely underdiagnosed pathological condition. As a consequence, bone fragility in men remains undertreated mainly due to the low screening frequency and to controversies in the bone mineral density (BMD) testing standards. Up to the 40% of overall osteoporotic fractures affect men, in spite of the fact that women have a significant higher prevalence of osteoporosis. In addition, in males, hip fractures are associated with increased morbidity and mortality as compared to women. Importantly, male fractures occur about 10 years later in life than women, and, therefore, due to the advanced age, men may have more comorbidities and, consequently, their mortality is about twice the rate in women. Gender differences, which begin during puberty, lead to wider bones in males as compared with females. In men, follicle-stimulating hormones, testosterone, estrogens, and sex hormone-binding levels, together with genetic factors, interact in determining the peak of bone mass, BMD maintenance, and lifetime decrease. As compared with women, men are more frequently affected by secondary osteoporosis. Therefore, in all osteoporotic men, a complete clinical history should be collected and a careful physical examination should be done, in order to find clues of a possible underlying diseases and, ultimately, to guide laboratory testing. Currently, the pharmacological therapy of male osteoporosis includes aminobisphosphonates, denosumab, and teriparatide. Hypogonadal patients may be treated with testosterone replacement therapy. Given that the fractures related to mortality are higher in men than in women, treating male subjects with osteoporosis is of the utmost importance in clinical practice, as it may impact on mortality even more than in women.

Key circular RNAs identified in male osteoporosis patients by whole transcriptome sequencing

Background Osteoporosis (OP) is a systemic disease with bone loss and microstructural deterioration. Numerous noncoding RNAs (ncRNAs) have been proved to participate in various diseases, especially circular RNAs (circRNAs). However, the expression profile and mechanisms underlying circRNAs in male osteoporosis have not yet been explored. Methods The whole transcriptome expression profile and differences in mRNAs, circRNAs, and microRNAs (miRNAs) were investigated in peripheral blood samples of patients with osteoporosis and healthy controls consisting of males ≥ 60-years-old. Results A total of 398 circRNAs, 51 miRNAs, and 642 mRNAs were significantly and differentially expressed in osteoporosis compared to healthy controls. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the host genes of significantly differentially expressed circRNAs were mainly enriched in the regulation of cell cycle process: biological process (BP), organelle part cellular components (CC), protein binding molecular function (MF), Toll-like receptor signaling pathway, tumor necrosis factor (TNF) signaling pathway, and thyroid hormone signaling pathway. circRNA-miRNA-mRNA regulatory network was constructed using the differentially expressed RNAs. Moreover, key circRNAs (hsa_circ_0042409) in osteoporosis were discovered and validated by qPCR. Conclusions The key cicrRNAs plays a major role in the pathogenesis of osteoporosis and could be used as potential biomarkers or targets in the diagnosis and treatment of osteoporosis.

Osteoporosis in Men: A Review of an Underestimated Bone Condition

Osteoporosis is called the ‘silent disease’ because, although it does not give significant symptoms when it is not complicated, can cause fragility fractures, with serious consequences and death. Furthermore, the consequences of osteoporosis have been calculated to weigh heavily on the costs of health systems in all the countries. Osteoporosis is considered a female disease. Actually, the hormonal changes that occur after menopause certainly determine a significant increase in osteoporosis and the risk of fractures in women. However, while there is no doubt that women are more exposed to osteoporosis and fragility fractures, the literature clearly indicates that physicians tend to underestimate the osteoporosis in men. The review of the literature done by the authors shows that osteoporosis and fragility fractures have a high incidence also in men; and, furthermore, the risk of fatal complications in hip fractured men is higher than that for women. The authors report the evidence of the literature on male osteoporosis, dwelling on epidemiology, causes of osteoporosis in men, diagnosis, and treatment. The analysis of the literature shows that male osteoporosis is underscreened, underdiagnosed, and undertreated, both in primary and secondary prevention of fragility fractures.

Age-dependent modulation of bone metabolism in zebrafish scales as new model of male osteoporosis in lower vertebrates

After middle age, in human bone, the resorption usually exceeds formation resulting in bone loss and increased risk of fractures in the aged population. Only few in vivo models in higher vertebrates are available for pathogenic and therapeutic studies about bone aging. Among these, male Danio rerio (zebrafish) can be successfully used as low vertebrate model to study degenerative alterations that affect the skeleton during aging, reducing the role of sex hormones. In this paper, we investigated the early bone aging mechanisms in male zebrafish (3, 6, 9 months old) scales evaluating the physiological changes and the effects of prednisolone, a pro-osteoporotic drug. The results evidentiated an age-dependent reduction of the mineralization rate in the fish scales, as highlighted by growing circle measurements. Indeed, the osteoblastic ALP activity at the matrix deposition site was found progressively downregulated. The higher TRAP activity was found in 63% of 9-month-old fish scales associated with resorption lacunae along the scale border. Gene expression analysis evidentiated that an increase of the tnfrsf1b (homolog of human rank) in aging scales may be responsible for resorption stimulation. Interestingly, prednisolone inhibited the physiological growth of the scale and induced in aged scales a more significant bone resorption compared with untreated fish (3.8% vs 1.02%). Bone markers analysis shown a significant reduction of ALP/TRAP ratio due to a prednisolone-dependent stimulation of tnfsf11 (homolog of human rankl) in scales of older fish. The results evidentiated for the first time the presence of a senile male osteoporosis in lower vertebrate. This new model could be helpful to identify the early mechanisms of bone aging and new therapeutic strategies to prevent age-related bone alterations in humans.

Effect of Selective Androgen Receptor Modulator Enobosarm on Bone Healing in a Rat Model for Aged Male Osteoporosis

Enobosarm (ostarine, MK-2866, or GTx-024) is a non-steroidal selective androgen receptor modulator. This study evaluated the effect of various regimens of enobosarm (EN) on bone healing in an orchiectomized rat model for aged male osteoporosis and compared it to testosterone (T) treatment. Ninety eight-month-old male Sprague Dawley rats were either orchiectomized (Orx) or left intact (Non-Orx) and divided into groups (n = 15/group): (1) Non-Orx; (2) Orx; (3) Orx+T-th; (4) Orx+EN-th; (5) Orx+T-pr; and (6) Orx+EN-pr. Prophylaxis (Pr) treatments were applied immediately after Orx for up to 18 weeks. Therapy (Th) treatments were applied 12 weeks after Orx for up to 6 weeks. Bilateral tibia osteotomy with plate osteosynthesis was performed 12 weeks after Orx in all groups. EN and T were mixed with the diet; the daily dosage was 0.35 ± 0.06 and 41 ± 8 mg/kg BW, respectively. Both T treatments improved bone healing by increasing callus volume and area, bone volume and density, and cortical width; they had no effect on prostate or levator ani weight. EN-pr increased the callus area and callus density and decreased cortical density, but increased prostate weight. The effect of T-pr and T-th on bone was stronger than EN-pr. EN-th affected bone healing negatively by reducing callus density and area and delaying osteotomy bridging. Levator ani weight was increased in both EN groups. EN treatment after fracture is not advisable in aged males. EN-pr treatment as a therapy for bone healing in men could be further investigated; endocrinological side effects must be closely monitored.

MANAGEMENT OF ENDOCRINE DISEASE: Male osteoporosis: diagnosis and management - should the treatment and the target be the same as for female osteoporosis?

Male osteoporosis has been neglected for too long time and there is need for a change. This condition is clearly under-estimated, under-diagnosed and under-treated. The diagnosis is often made late in the natural history of the pathology or even after a fracture event. Guidelines on screening politics do not agree whether and when men should be considered, and clinical trials are far less performed in men with respect to women. Actually, most of our knowledge on male osteoporosis, especially regarding treatment, is extrapolate from the female counterpart. Male osteoporosis is frequently secondary to other conditions and often associated with comorbidities. Therefore, identification of specific causes of male osteoporosis is essential to drive a correct and personalized treatment. Moreover, men have more osteoporosis-related complications and higher mortality rate associated with fractures. Furthermore, not only fewer men receive a correct and timely diagnosis, but also fewer men receive adequate treatment, and adherence to therapy is far less in men than in women. Of note, very few studies assessed the effect of antiosteoporotic treatments in men and most of them considered only bone density as primary endpoint. This review focuses on the areas that are still nebulous in male osteoporosis field, from identification of subjects who need to be evaluated for osteoporosis and screening programs dealing with primary prevention to diagnostic procedures for good estimates of bone quantity and quality and precise calculation of fracture risk and personalized treatment that take into account the pathophysiology of osteoporosis.