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The occurrence of multiple vertebral fractures after discontinuation of denosumab in the treatment of osteoporosis has reopened the debate on the optimal treatment duration and drug holidays.In principle, there is a difference in this regard between the discontinuation of medications such as bisphosphonates and substances without bone retention such as selective estrogen receptor modulators (SERMs), denosumab or teriparatide. Even after the end of application bisphosphonates have a very long half-life in the bones. After cessation of drug intake there is a slow, slight increase of bone turnover markers. Even after cessation of the SERM raloxifene, a decline in bone density can be observed, as with the termination of teriparatide. In contrast to these osteoporosis medications, after cessation of denosumab, a steep and rapid increase in markers of bone resorption above baseline levels (\"rebound\") and a reduction in bone mineral density to initial values can be observed.Osteoporosis is a disease that carries an increased risk of fracture, which is reduced for the duration of osteoporosis treatment. In certain situations, the fracture risk is only temporarily raised. In these situations, cessation of the osteoporosis treatment is possible. Beyond these special clinical situations, however, osteoporosis needs to be addressed as a chronic disease with a permanently increased fracture risk and the indication for therapy should be evaluated according to the extent of the risk of fracture.What happens after discontinuation of anti-osteoporosis drugs? The various effects on bone turnover markers, bone mineral density and fracture incidence of the individual drug groups are presented in detail, as are the resulting recommendations of the task forces of the American Society of Bone and Mineral Research (ASBMR) and the European Calcified Tissue Society (ECTS).The occurrence of multiple vertebral fractures after discontinuation of denosumab in the treatment of osteoporosis has reopened the debate on the optimal treatment duration and drug holidays.In principle, there is a difference in this regard between the discontinuation of medications such as bisphosphonates and substances without bone retention such as selective estrogen receptor modulators (SERMs), denosumab or teriparatide. Even after the end of application bisphosphonates have a very long half-life in the bones. After cessation of drug intake there is a slow, slight increase of bone turnover markers. Even after cessation of the SERM raloxifene, a decline in bone density can be observed, as with the termination of teriparatide. In contrast to these osteoporosis medications, after cessation of denosumab, a steep and rapid increase in markers of bone resorption above baseline levels (\"rebound\") and a reduction in bone mineral density to initial values can be observed.Osteoporosis is a disease that carries an increased risk of fracture, which is reduced for the duration of osteoporosis treatment. In certain situations, the fracture risk is only temporarily raised. In these situations, cessation of the osteoporosis treatment is possible. Beyond these special clinical situations, however, osteoporosis needs to be addressed as a chronic disease with a permanently increased fracture risk and the indication for therapy should be evaluated according to the extent of the risk of fracture.What happens after discontinuation of anti-osteoporosis drugs? The various effects on bone turnover markers, bone mineral density and fracture incidence of the individual drug groups are presented in detail, as are the resulting recommendations of the task forces of the American Society of Bone and Mineral Research (ASBMR) and the European Calcified Tissue Society (ECTS).

Almost 50 % of osteoporosis (OP) patients discontinue bisphosphonate (BP) therapy within 1–2 years after the start of their treatment. Denosumab’s longer dosing interval with its administration every 6 months (Q6M) as a subcutaneous (sc) injection might result in a better real-life treatment adherence and persistence than weekly or monthly oral BP treatment regimen. The objectives of this open, investigator-initiated, prospective, observational, single-center study were to evaluate adherence with denosumab 60 mg sc every 6 months (Q6M) (Prolia ® ) injections in osteoporotic patients in a routine clinical care setting and to describe whether positive feedback to OP patients based on measured bone mineral density (BMD) increases and good safety profile have an impact on patients’ real-life adherence. Results indicate that the rarity of adverse events and reduced dosage frequency together with the consistency of rapid and highly significant increases in BMD already after 6 months of denosumab therapy used as a positive reinforcement during doctor–patient interactions had a significant, positive impact on osteoporotic patient’s adherence to continue with the 6-monthly sc denosumab injections.

Summary Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. Introduction To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. Methods A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 μg/day, n  = 45) and risedronate (35 mg/week, n  = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. Results PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. Conclusions Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.

Osteoporosis is prevalent in men with an estimated one in eight men older than 50 years suffering from osteoporotic fracture, and a higher mortality rate after fracture among men compared with women. There are few approved therapies for osteoporosis in men. This observational study assesses the efficacy and safety of risedronate in the treatment of men with primary and secondary osteoporosis. A single-center, open label, randomized, prospective 1-year study was conducted in men with primary or secondary osteoporosis. Patients were randomized to risedronate (risedronate 5 mg/day plus calcium 1,000 mg/day and vitamin D 800 IU/day) or control groups (alfacalcidol 1 mug/day plus calcium 500 mg/day or vitamin D 1,000 IU/day plus calcium 800 mg/day). Bone mineral density (BMD) measurements, X-rays of the spine, a medical history and physical exam, and patient self-assessments of back pain were performed at baseline and 12 months. Blinded semi-quantitative fracture assessment was conducted by a radiologist. A total of 316 men with osteoporosis were enrolled in the trial (risedronate, n=158; control, n=158). At 1 year lumbar spine BMD increased by 4.7% in the risedronate group versus an increase of 1.0% in the control group (P<0.001). Significant increases in BMD at the total hip and femoral neck were also observed with risedronate compared with the control group. The incidence of new vertebral fracture in the risedronate group was reduced by 60% versus the control group (P=0.028). Daily treatment with risedronate for 12 months significantly increased BMD at the lumbar spine, femoral neck and total hip and significantly reduced the incidence of new vertebral fractures. This is the first prospective, randomized, controlled trial to demonstrate a significant reduction in vertebral fractures in 1 year in men with primary or secondary osteoporosis.

A combined therapy with the strongly antiresorptive Alendronate and the pleiotropically acting D-hormone analogue Alfacalcidol may have additive effects on bone quality, falls and fracture risk in established osteoporosis. The aim of this study (Alfacalcidol Alendronate Combined-AAC) was to compare the efficacy and safety of a combined parallel therapy with Alendronate and Alfacalcidol to the treatment with either Alendronate in combination with plain vitamin D or Alfacalcidol alone in patients with established postmenopausal or male osteoporosis. Ninety patients were included as matched triplets to receive randomly either 1 microg Alfacalcidol daily + 500 mg calcium (group A, n = 30) or 70 mg Alendronate weekly + 1,000 mg calcium + 1,000 IU vitamin D daily (group B, n = 30) or 1 microg Alfacalcidol daily + 70 mg Alendronate weekly + 500 mg calcium daily (group C, n = 30). Patients were recruited in one centre and were followed up for 24 months. Analysis was intention-to-treat and the primary outcome was lumbar spine and total hip bone mineral density (measured observer blind). BMD was measured at the lumbar spine and at the proximal femur with dual energy X-ray absorptiometry (LUNAR Prodigy, GE, USA) at the beginning and after 12 and 24 months. During the 2-year-study we observed descriptively significant increases at the lumbar spine of 3.0% in group A compared to baseline, of 5.4% in group B and of 9.6% in group C, respectively. The superiority of the Alendronate + Alfacalcidol treatment group over Alfacalcidol alone and over Alendronate + vitamin D was of more than large rele-vance (both tests: MW > 0.71; CI-LB > 0.64; P < 0.001). We also observed median increases of the BMD at the total hip of 1.5% in group A, of 2.4% in group B and of 3.8% in group C, respectively. The superiority of group C over group A and over group B again was relevant and statistically significant in a descriptive sense. After 2 years there was a tendency towards higher rates of vertebral and non-vertebral fractures in group A and B as compared to C. Taking both fracture types together we observed 9, 10 and 2 \"osteoporotic fractures\" in groups A, B and C, respectively. The comparison of group C with pooled groups A and B and with each single group gave a relevantly lower fracture rate for the combination of Alendronate and Alfacalcidol. Furthermore a lower rate of falls was observed for the combination Alendronate plus Alfacalcidol versus Alendronate + vitamin D, but not versus Alfacalcidol alone. We found 80% of the patients in the Alendronate + Alfacalcidol group free from back pain at month 24, compared to 30% in the Alendronate + vitamin D and 43% in the Alfacalcidol monotherapy group. The superiority is relevant (both tests: MW > 0.64; CI-LB > 0.56; P < 0.003). Pain decrease also occurred more rapidly in the Alendronate + Alfacalcidol group than in the other groups. In general side effects in all groups were mild, and only four cases of moderate hypercalcuria in group A and one in group C were reported, but no case of hypercalcemia was documented. In conclusion, the combination therapy with Alendronate and Alfacalcidol exhibited superiority in terms of BMD, overall fractures, rate of falls and back pain over either Alendronate in combination with plain vitamin D or Alfacalcidol alone. The overall safety profiles of the three treatment regimens were found to be not different in this study.

For most three-dimensional analytical solutions proposed for the extrusion of shaped sections, the axial component of the velocity vector has been assumed to be constant at each cross section throughout the deforming zone. This shortcoming means that these velocity fields are not in accordance with the reality of the extrusion problem, and hence, the upper bounds based on such fields give high values for the extrusion pressure. To overcome this, a new formulation has been presented in this paper for which a kinematically admissible velocity field has been developed using a variable axial velocity component. For this purpose, curved surfaces of velocity discontinuities at the entry and exit have been proposed and incorporated into the formulation for the extrusion of shaped sections from circular billets. As an example, a square profiled section has been chosen for the extrusion problem. The upper bound on extrusion pressure was computed using the new formulation. It was shown that the initial velocity discontinuity surface at the entry to the deforming region was flat, and as one travels into the deforming region towards the exit section, the velocity discontinuity surface gradually became convex, having the highest convexity at the exit section. This was contrary to what has been suggested in the literature so far. The measure of convexity depends on the extrusion parameters which have been investigated in this work. Experiments were also carried out to verify the theoretical results, and good agreements were observed between the two. Comparison of the present results with similar previous works showed good improvements as well.

Due to pleiotropic-synergistic actions on bone, muscle, gut, brain and different other non-skeletal tissues, alfacalcidol is an interesting drug for treating osteoporosis. In studies on glucocorticoid-induced osteoporosis, men have always been treated with calcitriol or this active D-hormone prodrug, but there is no study of male patients only in the literature. The AIM-Trial (Alfacalcidol In Men) is an extension of the control group ( n  = 158) of our former risedronate study in male osteoporosis (Ringe et al. in Rheumatol Int 29:311–315, 2009 ). In that study, we treated daily those controls with prevalent vertebral fractures with 1 μg alfacalcidol + 500 mg calcium (group A) and those without prevalent vertebral fractures with 1,000 IU plain vitamin D (Vit. D) + 1,000 mg calcium (group B). Subsequently, we added an additional 56 pairs of patients to these two groups: 28 with and 28 without prevalent vertebral fractures, reaching a total of 214 cases. That means with this design, we are comparing two groups with a different risk at onset. Due to the prevalent vertebral fractures and lower average bone mineral density (BMD) values, there was a higher risk of incident fractures in group A. After 2 years, we found significantly higher increases in lumbar spine BMD (+3.2 vs. +0.8 %) and total hip BMD (+1.9 vs. −0.9 %) in group A and B, respectively. Eighteen incident falls were recorded in the alfacalcidol group and 38 in the group treated with Vit. D ( p  = 0.041). There were significantly lower rates of patients with new vertebral and non-vertebral fractures in group A than in group B. Back pain was significantly reduced only with alfacalcidol. Concerning the incidence of new non-vertebral fractures, we found that there was a relation to renal function in the two groups. The advantage for alfacalcidol was mainly due to a higher non-vertebral fracture-reducing potency in patients with a creatinine clearance (CrCl) below 60 ml/min ( p  = 0.0019). There were no serious adverse events (SAE), and the numbers of mild-to-moderate adverse events (AE) were not different between groups. Despite the higher initial fracture risk in the alfacalcidol group, 2-year treatment with this active D-hormone prodrug showed a higher therapeutic efficacy in terms of BMD, falls and fractures. One important advantage of alfacalcidol may be that it is effective even in patients with mild-to-moderate renal insufficiency.

Zusammenfassung Das Auftreten multipler Frakturen nach Absetzen von Denosumab bei der Behandlung der Osteoporose hat die Diskussion um Therapiedauer und Therapiepausen neu entfacht. Prinzipiell unterscheidet sich bei dieser Betrachtung das Absetzen von Medikamenten mit ossärer Retention wie den Bisphosphonaten von Substanzen ohne Knochenretention wie Östrogenen, selektiven Östrogen-Rezeptor-Modulatoren (SERM), Denosumab oder Teriparatid. Bisphosphonate haben auch nach Beendigung der Applikation eine sehr lange Halbwertszeit im Knochen. Nach Absetzen kommt es zu einem langsamen und leichten Anstieg der Knochenumbaumarker. Auch nach Absetzen von Raloxifen aus der Gruppe der SERM ist ein Rückgang der Knochendichte zu beobachten, wie auch nach Teriparatid-Beendigung. Im Gegensatz zu diesen Osteoporosemedikamenten ist nach Absetzen von Denosumab ein starker und rascher Anstieg der Knochenmarker über das Baseline-Niveau und ein Absinken der Knochendichte auf Ausgangswerte zu beobachten („Rebound“). Osteoporose ist eine Erkrankung mit erhöhtem Frakturrisiko, welches für die Dauer der Osteoporosetherapie reduziert wird. In bestimmten Situationen ist das Frakturrisiko nur passager erhöht. Hier ist ein Absetzen der Osteoporosetherapie denkbar. Außerhalb dieser Konstellationen ist die Osteoporose jedoch als chronische Erkrankung mit dauerhaft erhöhtem Frakturrisiko zu betrachten und die Therapieindikation je nach Höhe des Frakturrisikos zu evaluieren. Was passiert nach Absetzen von Antiosteoporotika? Die unterschiedlichen Effekte auf Knochenmarker, Knochendichte und Frakturinzidenz der einzelnen Substanzgruppen sowie die resultierenden Empfehlungen der Task Forces der American Society of Bone and Mineral Research (ASBMR) und der European Calcified Tissue Society (ECTS) werden detailliert aufgezeigt.

Zusammenfassung Hintergrund Die männliche Osteoporose zählt mit über 1 Mio. Betroffener in Deutschland nicht zu den seltenen Erkrankungen. Osteoporotische Frakturen haben bei Männern eine höhere Mortalität als bei Frauen, werden aber selten abgeklärt oder einer spezifischen Therapie zugeführt. Fragestellung Betrachtet werden die Epidemiologie der männlichen Osteoporose, die Versorgungssituation, pathophysiologische Aspekte auf hormoneller Ebene, Risikofaktoren, diagnostische Abklärung und therapeutische Optionen. Material und Methode Es erfolgen ein Überblick über die aktuelle Datenlage zur männlichen Osteoporose, Empfehlungen zur Diagnostik und eine Darstellung der Studienlage zur medikamentösen Therapie. Ergebnisse Bei Männern ist eine gezielte Anamnese zur Erfassung der Risikofaktoren erforderlich, da in 50–70 % der Fälle Osteoporoserisikofaktoren vorliegen. Da jeder zehnte Mann über 50 Jahre eine Wirbelfraktur erlitten hat und viele Frakturen häufig unerkannt geblieben sind, beinhaltet die radiologische Primärdiagnostik eine Bildgebung der Wirbelsäule. Zur differenzialdiagnostischen Abgrenzung ist das osteologische Labor von Bedeutung. Als Therapieoptionen stehen in Deutschland der aktive Vitamin-D-Metabolit Alfacalcidol, Alendronsäure und Risedronsäure als orale Bisphosphonate, Zoledronsäure als i.v.-Bisphosphonat, Strontiumranelat sowie als s.c.-Injektion der antiresorptiv wirksame Rank-Ligand-Antikörper Denosumab und das osteoanabol wirksame Teriparatid zur Verfügung. Schlussfolgerungen Die männliche Osteoporose muss als sozioökonomisch bedeutendes, abklärungs- und behandlungsbedürftiges Krankheitsbild wahrgenommen werden. Das breite Spektrum wissenschaftlich sehr gut belegter medikamentöser Behandlungsoptionen verpflichtet zu einer differenzierten, individuellen Therapie von Männern mit Osteoporose.

Osteoporosis in men is an important public health problem with more than 1 million cases in Germany. Although osteoporotic fractures have a much higher mortality in men than in women, male patients are still underdiagnosed and undertreated. Epidemiology of male osteoporosis and current treatment situation, pathophysiological aspects at the hormonal level, risk factors, diagnostic work-up and therapeutic options. Overview of data concerning male osteoporosis, recommendations for diagnostic work-up and presentation of the study situation on pharmaceutical therapies. As risk factors for osteoporosis are present in 50-70 % of male patients, a detailed patient history is necessary for assessment of the risk factors. Radiological imaging of the spine is primarily recommended to identify individuals with prevalent vertebral fractures, as approximately 10 % of males above the age of 50 years have suffered a vertebral fracture. Laboratory testing of relevant parameters helps to rule out other metabolic bone diseases. In Germany, specific medications available for the treatment of male osteoporosis comprise the active vitamin D analogue alfacalcidol, the oral bisphosphonates alendronate and risedronate, the intravenous biphosphonate zoledronic acid, the anti- receptor activator of NF-κB ligand (RANKL) antibody denosumab, which can be given as intravenous injection and strontium ranelate, a drug with a complex mode of action. Teriparatide, a recombinant form of the 34 N-terminal amino acid sequence of parathyroid hormone is the only anabolic agent approved for male osteoporosis. Osteoporosis in men is increasingly being recognized as an important public health problem and affected patients need to be adequately diagnosed and treated. Nowadays, a broad spectrum of well-proven therapeutic options with different modes of action allow individual treatment strategies for male osteoporosis patients.