Alfacalcidol in men with osteoporosis: a prospective, observational, 2-year trial on 214 patients.

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.

[Vitamin D deficiency in Germany, is it a danger for increased morbidityand mortality?]. / Vitamin-D-Unterversorg ung in Deutschland. Gefahr für erhöhte Morbidität und Mortalität?

Vitamin D regulates the calcium-phosphate metabolism and thereby plays an important role for the integrity and functioning of bone, muscle and nerves. Studies have shown furthermore an influence on certain types of cancer, diabetes and cardiovascular diseases. Vitamin D is mainly produced by the skin. During exposure to sunlightthe precursor7-dehydrocholesterol is transformed to colecalciferol (vitamin D3). Smaller amounts are supplied by nutrition. In our latitude vitamin D synthesis takes only place during summertime. The vitamin stored in fat tissue in generally is not sufficient for the whole winter period and accordingly insufficiency is very frequent. In a cross-sectional study all over Germany (DeViD, 2007) only about 8% of the population was vitamin D sufficient in spring time.Two prospective studies (2008) proved a correlation between vitamin D supply and overall mortality. An amelioration of vitamin D supply can be achieved either by increasing sun exposure or daily oral intake of 800-2000 IU (=20-50 microg) colecalciferol.

Strontium ranelate: an effective solution for diverse fracture risks.

Osteoporosis is listed by the WHO among the ten most frequent and socio-economically important, chronic diseases of mankind. The term osteoporosis however comprises a number of different pathophysiological conditions and clinical situations of weakened bones with increased risk of fragility fractures. A modern anti-osteoporotic drug should provide qualified study results proving therapeutic efficacy over this broad range of daily clinical appearances of osteoporosis. The decision for treatment in the individual patients depends no longer only on bone mineral density. Today, the major criterion for decision making is the prospective 10-year risk for fractures. Since this risk is calculated on the basis of age, sex, bone mineral density, prevalent fractures, and a number of other contributing risk factors (Kanis et al., Osteoporos Int 12:989-995, 2001; Kanis et al., Osteoporos Int 19:385-397, 2008), it seems to be of interest to have a look whether the fracture-reducing potency of a drug is influenced by these risk factors. The purpose of this review is to analyze whether the fracture-reducing efficacy of strontium ranelate in patients with osteoporosis can be achieved independently of sex, etiology of osteoporosis, and the major diagnostically relevant risk factors.

A review of bone pain relief with ibandronate and other bisphosphonates in disorders of increased bone turnover.

Several disorders of increased bone turnover and low bone mineral density (BMD) are associated with severe pain that is refractory to treatment with conventional and even opioid analgesics. Because of their ability to effectively improve the underlying pathogenesis of these disorders (i.e., reduce bone resorption and increase BMD), bisphosphonates are considered part of the palliative care of malignant bone-related pain and also appear to have some analgesic efficacy in other, non-malignant conditions. Ibandronate, a potent, nitrogen-containing bisphosphonate that can be given orally and intravenously, has demonstrated robust effects in relieving the pain associated with several malignant disorders. Unlike other available intravenous (i.v.) bisphosphonates, i.v. ibandronate is not associated with renal side effects, even at high doses such as 6 mg every 3 weeks. In addition, oral ibandronate (50 mg daily) is currently the only oral bisphosphonate proven to reduce and maintain bone pain scores below baseline for 2 years in patients with metastatic bone disease. Lower dose, less intense dosing regimens of ibandronate relieve bone pain in non-malignant conditions: i.v. ibandronate (2 mg every 3 months with or without an initial 4 mg injection) provides pain relief for patients with corticosteroid-induced osteoporosis, localised transient osteoporosis (bone marrow oedema) and sternocostoclavicular hyperostosis. Both oral and i.v. ibandronate are well tolerated. In conclusion, ibandronate offers an effective and convenient choice for the relief of bone pain in a wide variety of underlying bone conditions.

Efficacy of risedronate in men with primary and secondary osteoporosis: results of a 1-year study.

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.

Effective and rapid treatment of painful localized transient osteoporosis (bone marrow edema) with intravenous ibandronate.

Localized transient osteoporosis (LTO; bone marrow edema syndrome) is a rare disorder of generally unknown etiology that is characterized by acute onset of disabling bone pain. Treatment options are currently limited and largely ineffective. The locally increased bone turnover and low bone mineral density (BMD) typical of LTO indicate a potential role for bisphosphonate therapy. Ibandronate, a potent nitrogen-containing bisphosphonate, has proven efficacy in the management of postmenopausal osteoporosis and corticosteroid-induced osteoporosis when administered as a convenient intermittent intravenous (i.v.) injection with a between-dose interval of 2 or 3 months. In a study of 12 patients with LTO, ibandronate was administered as an initial 4-mg i.v. dose with a second, optional injection of 2 mg at 3 months. Daily calcium and vitamin D supplements were provided. Pain was measured at baseline and at 1, 2, 3, and 6 months using a visual analog scale (VAS) of 1-10, and BMD was measured at baseline and 6 months. I.v. ibandronate provided rapid and substantial pain relief. The mean (SD) VAS score decreased from 8.4 (1.3) at baseline to 0.5 (0.7) at 6 months, at which time seven patients had achieved complete pain relief. At 6 months, mean lumbar spine BMD had increased by 4.0% (range -0.8 to 7.7%) in the overall population. I.v. ibandronate injection affords advantages over currently available oral and i.v. bisphosphonates and thus offers a promising therapeutic advance in the treatment of LTO.

Intermittent intravenous ibandronate injections reduce vertebral fracture risk in corticosteroid-induced osteoporosis: results from a long-term comparative study.

Despite its well-known benefits, chronic corticosteroid therapy causes osteoporotic fractures in approximately 30-50% of patients treated. To prevent the occurrence of these fractures, treatment with oral bisphosphonates is recommended. However, current oral bisphosphonates, which are given either daily or weekly, are associated with stringent, inconvenient dosing guidelines. Less frequent dosing may provide greater acceptability. The objective of this study was to investigate the efficacy and safety of ibandronate, a highly potent nitrogen-containing bisphosphonate, when given by intravenous (i.v.) injection every 3 months in men and women with established corticosteroid-induced osteoporosis (CIO; lumbar spine [L2-L4] bone mineral density [BMD] T-score < or =-2.5). A total of 115 participants were assigned to receive daily calcium supplements (500 mg) plus either ibandronate (2 mg) injections every 3 months or daily oral alfacalcidol (1 microg), for 3 years. Intermittent i.v. ibandronate injections produced significantly greater increases in mean BMD at the lumbar spine (13.3% versus 2.6%, respectively; p<0.001), and femoral neck (5.2% versus 1.9%, respectively; p<0.001) versus daily oral alfacalcidol, after 3 years, relative to baseline. This study was not statistically powered to show a difference between the groups with respect to fracture incidence. Nevertheless, after 36 months, the frequency of patients with new vertebral fractures was significantly lower in the patients receiving ibandronate relative to those taking alfacalcidol (8.6% versus 22.8%, respectively; p=0.043). This is the first time that significant vertebral fracture reduction has been demonstrated with an i.v. bisphosphonate in CIO. Patients treated with i.v. ibandronate injections also experienced less back pain (p<0.001) and less height loss (p=0.001) than those receiving oral alfacalcidol. Both regimens were well tolerated. In conclusion, intermittent i.v. ibandronate injections are efficacious, well-tolerated, and convenient, and promise to offer physicians an important therapeutic advance in the management of osteoporosis.

Three-monthly ibandronate bolus injection offers favourable tolerability and sustained efficacy advantage over two years in established corticosteroid-induced osteoporosis.

OBJECTIVE: Corticosteroids are widely prescribed, although treatment-related side-effects are common. Of these adverse events (AEs), osteoporosis is considered the most serious. Currently, oral bisphosphonates are the standard treatment for corticosteroid-induced osteoporosis (CIO). However, intermittent intravenous (i.v.) therapy may have advantages, including lack of gastrointestinal AEs, improved bioavailability and increased compliance. This study investigated the efficacy and safety of 3-monthly i.v. ibandronate bolus injections in patients with established CIO. The results from a planned 2-yr interim analysis are reported. METHOD: In this controlled, prospective, open-label, parallel-group study, 104 patients (49 men and 55 women) with established CIO (mean T-score <-2.5 s.d. at the lumbar spine (L2-L4) received daily calcium (500 mg) plus either 3-monthly i.v. ibandronate (2 mg) bolus injections or oral daily alfacalcidol (1 micro g). The primary end-point was bone mineral density (BMD) change at the lumbar spine, femoral neck and calcaneus after 24 months. RESULTS: Compared with oral daily alfacalcidol, i.v. ibandronate produced significantly superior gains in mean (+/-s.d.) BMD at the lumbar spine (2.2+/-3.1 vs 11.9+/-7.4%; P<0.001), femoral neck (1.3+/-1.8 vs 4.7+/-4.0%; P<0.001) and calcaneus (7.6+/-3.8 vs 15.5+/-10.7%; P<0.0001) after 2 yr. Consistent with these BMD gains and, although the study was not powered for fractures, a trend towards a reduction in vertebral fractures and greater back pain relief was seen in the ibandronate group. The overall incidence of AEs was similar in the two treatment arms. CONCLUSIONS: Three-monthly i.v. ibandronate bolus injections are significantly superior to alfacalcidol in the treatment of CIO. These data confirm the potential of ibandronate for the treatment of osteoporosis associated with corticosteroid use. The ease of administration, lack of AEs and good compliance associated with intermittent i.v. ibandronate make it a potentially valuable alternative to oral bisphosphonate therapy for the treatment of CIO.

Transdermal fentanyl for the treatment of back pain caused by vertebral osteoporosis.

Pain relief for patients with osteoporosis is important to maintain mobility and facilitate physical therapy. Transdermal fentanyl may be useful but has not been studied systematically. Patients with at least one osteoporotic vertebral fracture requiring strong opioids were enrolled and received transdermal fentanyl. Treatment history, pain, ease of physical therapy, and quality of life were recorded at baseline and after 4 weeks. Of 64 patients enrolled, 49 completed the study; 12 withdrew because of adverse events, most commonly nausea, vomiting, or dizziness. Pain at rest and on movement decreased significantly from baseline to final assessment (mean scores 7.84 and 8.55, respectively, at baseline, falling to 3.56 and 4.50 after 4 weeks). Quality of life improved significantly, and 61% of patients were satisfied with the treatment. Ability to undergo physical therapy improved significantly. Transdermal fentanyl is useful for the treatment of severe back pain caused by osteoporosis.

[Osteomalacia in immigrants: therapeutic management of two cases]. / Immigrantenosteomalazie. Zwei Fallvorstellungen mit Therapieverlauf.

BACKGROUND: Vitamin D deficiency in immigrant adults eventually leads to an osteomalacia syndrome with its characteristic clinical features of bone pain, muscle weakness and difficulty in walking (waddling gait). CASE REPORT: We report on 2 female immigrants from Ethiopia and Eritrea who developed the typical clinical signs of osteomalacia such as generalized bone pain and muscle weakness. Also in osteomalacia there is a significant decrease in bone density but more relevant for diagnosis are low serum levels of 25-OH-vitamin D and as radiological features pseudofractures (Looser's zones). Bone biopsy definitely proves the diagnosis. Simple treatment with vitamin D and calcium is highly effective. CONCLUSION: Since there is an increasing number of immigrants into northern European countries osteomalacia should always be taken into consideration if such patients develop skeletal pain syndrome and muscle weakness.

Avoidance of vertebral fractures in men with idiopathic osteoporosis by a three year therapy with calcium and low-dose intermittent monofluorophosphate.

There are currently no trial-based recommendations for the treatment of idiopathic osteoporosis in men. A prospective, controlled, randomized 3-year study was conducted to evaluate the effects of intermittent, low-dose fluoride combined with continuous calcium supplementation on bone mass and future fracture events in men with this disease. Sixty-four men with idiopathic osteoporosis (mean age 53 years; mean T-score at L2-4, -2.75) and no previous vertebral fractures were randomly assigned to two treatment groups. Group A received intermittent (3 months on, 1 month off) treatment with monofluorophosphate 114 mg/day (i.e. 15 mg fluoride ions) plus continuous calcium supplementation (950-1000 mg/day). Group B received continuous calcium (1000 mg/day) alone. Bone mineral density was measured at the lumbar spine, hip and radius at 6-months intervals; thoracic and lumbar spine radiographs were obtained every 12 months. In group A bone density increased at all sites (by between +1.2% and +8.8%), while group B showed moderate decreases (by between -1.4% and -5.2%). After 36 months, bone densities at all sites in group A were significantly higher than those of group B. Three patients (10%) in group A suffered a total of 4 vertebral fractures versus 12 patients (40%) with 17 fractures in group B (p = 0.008). Non-vertebral fractures occurred in 3 patients in group A versus 11 in group B, though this difference was not significant. Back pain was significantly reduced in group A and unchanged in group B (after 3 years p = 0.0003). All side-effects were mild and transient. Early treatment of idiopathic osteoporosis in the male using the fluoride-calcium regimen we tested can improve cancellous and cortical bone density, reduce the incidence of vertebral fractures and attenuate back pain.

[Severe osteomalacia in endemic sprue. An important differential diagnosis in osteoporosis]. / Schwere Osteomalazie bei einheimischer Sprue. Eine wichtige Differentialdiagnose bei V. a. Osteoporose.

A 67-year-old woman has a 20-year history of recurrent abdominal pain, diarrhea and diffuse bone pain. During the course of numerous hospitalisations the diagnoses "iron deficiency anemia", "iron absorption disorder", "osteoporosis" and "hyperparathyroidism" had been made. Despite treatment with vitamin D3, calcium, fluorides and iron, the patient's condition deteriorated to such a degree that she became in need of constant care. After 20 years of illness, nontropical sprue (celiac disease) with secondary intestinal osteopathy was identified. High-dose parenteral treatment with vitamin D3, oral calcium supplementation and a gluten-free diet resulted in an improvement of the patient's condition within three months, and the patient can now largely look after herself again.

[Pathogenesis of postmenopausal osteoporosis]. / Pathogenese der postmenopausalen Osteoporose.

Low peak bone mass and increased bone loss within the process of bone remodelling are the most important determinants for the manifestation of postmenopausal osteoporosis. Both are influenced during lifetime by a large number of risk factors additively leading to a critical low bone mass. Loss of bone substance and deterioration of architecture of bone tissue lead to an increased fragility of the skeleton. In this complex interactions menopausal decrease of endogenous estrogen secretion is of special importance. Decrease of estrogen induces by effects on calcitropic hormones and different local growth factors a high bone turnover with a high rate of bone loss. The resulting slight increase of serum calcium and the consequent decrease in the secretion of parathyroid hormones and activation of vitamin D in the kidneys lead to a decreased intestinal calcium absorption. In peri- and early postmenopausal women there is a large range of different degrees of bone turnover. It is unclear however, whether there are really two distinct groups of so-called rapid and slow bone losers. It remains to clarify which intrinsic mechanisms besides the risk factors are responsible for the individually different answer of calcium and bone metabolism to estrogen deficiency, which is the same in every women.

[Osteoporosis in men. Pathogenesis and clinical classification of 254 cases]. / Osteoporose bei Männern. Pathogenese und klinische Einteilung bei 254 Fällen.

In a prospective study, 321 consecutive male patients, aged between 16 and 86 years, referred to the Department of Medicine of the Medical Centre at Leverkusen from many parts of Germany over a three-year period with the diagnosis of osteoporosis, underwent a standardized programme of clinical investigation: 254 (79%) were found to have the condition. The programme consisted of a detailed history, physical examination, a battery of laboratory tests, X-ray examination of the skeleton and osteodensitometry. Where, as a result, underlying disease or risk factors were suspected, further tests were performed. 98 patients (39%) were found by densitometric criteria to have preclinical, 156 (61%) manifest osteoporosis with one or more vertebral body fractures. There was no significant difference regarding bone density between the preclinical and manifest cases. 76 of the 254 (30%) patients had no detectable pathogenetic factors, i. e. their osteoporosis was classified as idiopathic (mean age 51 years), while as senile osteoporosis in 16 elderly patients (mean age 78 years). The remaining 162 patients had 286 risk factors within 24 different categories. Depending on duration, intensity and combination of these risk factors, the osteoporosis was classified as primary with few risk factors or as secondary osteoporosis of single or multiple aetiology (mean age of these three groups was 51, 56 and 52 years, respectively). The most important demonstrable risk factors were (in decreasing order of frequency) glucocorticoid treatment, alcohol consumption, smoking, hypogonadism, hypercalciuria, liver disease, Crohn's disease, low calcium nutrition, hyperthyroidism, physical inactivity, stomach operation and plasmacytoma.--This study indicates that if there is evidence of significant risk factors detailed bone densitometry should be performed so that any necessary treatment can be initiated early. If there is known osteoporosis, staging and exact analysis of risk factors is a precondition for any cause-oriented treatment.

[The avoidance of early postmenopausal bone substance losses by transdermal estrogen substitution]. / Vermeidung früh-postmenopausaler Knochensubstanzverluste durch transdermal Ostrogensubstitution.

The effect of transdermal oestrogen replacement therapy on prevention of osteoporosis was investigated in a controlled randomized study of 38 healthy women (mean age 49.6 [45-54] years) in the early postmenopausal period (< or = 3 years). 19 women (hormone group) continuously used oestrogen patches with a mean daily estradiol delivery of 0.05 mg with addition of medroxyprogesterone acetate, 5 mg orally, for 14 days per month. The other 19 women (calcium group), whose baseline levels were identical, took 500 mg calcium daily. Climacteric symptoms improved significantly in the hormone group, and serum and urinary calcium levels and total serum cholesterol all declined, while the HDL cholesterol levels increased slightly. Bone density was measured by single photon absorptiometry at two points (1/3 and 1/10 of the forearm length from the distal end of the radius). After 6 and 12 months, the values at the proximal site (1/3) had risen in the hormone group by 1.1% and 0.46% and had fallen in the calcium group by 1.96% and 2.42% respectively (both P < 0.05 vs hormone group). At the distal radial site (1/10), the values increased by 2.14% and 5.3% in the same period and fell by 3.59% and 5.67% in the calcium group. The overall difference after 12 months was 11% (P < 0.01). Transdermal oestrogen appears to be as effective as oral oestrogen replacement for prevention of osteoporosis, and should help to prevent vertebral and limb fractures in the elderly.