Johann D. Ringe

Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO)

Abstract Background: Vitamin D insufficiency has deleterious consequences on health outcomes. In elderly or postmenopausal women, it may exacerbate osteoporosis. Scope: There is currently no clear consensus on definitions of vitamin D insufficiency or minimal targets for vitamin D concentrations and proposed targets vary with the population. In view of the potential confusion for practitioners on when to treat and what to achieve, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) convened a meeting to provide recommendations for clinical practice, to ensure the optimal management of elderly and postmenopausal women with regard to vitamin D supplementation. Findings: Vitamin D has both skeletal and extra-skeletal benefits. Patients with serum 25-hydroxyvitamin D (25-(OH)D) levels <50 nmol/L have increased bone turnover, bone loss, and possibly mineralization defects compared with patients with levels >50 nmol/L. Similar relationships have been reported for frailty, nonvertebral and hip fracture, and all-cause mortality, with poorer outcomes at <50 nmol/L. Conclusion: The ESCEO recommends that 50 nmol/L (i.e. 20 ng/mL) should be the minimal serum 25-(OH)D concentration at the population level and in patients with osteoporosis to ensure optimal bone health. Below this threshold, supplementation is recommended at 800 to 1000 IU/day. Vitamin D supplementation is safe up to 10,000 IU/day (upper limit of safety) resulting in an upper limit of adequacy of 125 nmol/L 25-(OH)D. Daily consumption of calcium- and vitamin-D-fortified food products (e.g. yoghurt or milk) can help improve vitamin D intake. Above the threshold of 50 nmol/L, there is no clear evidence for additional benefits of supplementation. On the other hand, in fragile elderly subjects who are at elevated risk for falls and fracture, the ESCEO recommends a minimal serum 25-(OH)D level of 75 nmol/L (i.e. 30 ng/mL), for the greatest impact on fracture.

Avoidance of Vertebral Fractures in Men with Idiopathic Osteoporosis by a Three Year Therapy with Calcium and Low-Dose Intermittent Monofluorophosphate

Abstract. There are currently no trial-based recommendations for the treatment of idiopathic osteoporosis in man. 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 hither 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.

Comparative effects of teriparatide and risedronate in glucocorticoid-induced osteoporosis in men: 18-month results of the EuroGIOPs trial.

Data on treatment of glucocorticoid‐induced osteoporosis (GIO) in men are scarce. We performed a randomized, open‐label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T‐score ≤ –1.5 standard deviations. Subjects received 20 μg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L1–L3) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high‐resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X‐ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this 18‐month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE‐derived strength than risedronate.

Treatment of Glucocorticoid-Induced Osteoporosis with Alfacalcidol/Calcium Versus Vitamin D/Calcium

Abstract. Vitamin D/calcium substitution is generally regarded as an effective first step treatment for glucocorticoid-induced osteoporosis (GIOP). The aim of our study was to evaluate the efficacy of the active vitamin D metabolite alfacalcidol (1α) compared with the native vitamin D3 in patients with established GIOP with or without vertebral fractures. Patients on long-term corticoid therapy were given either 1 μg alfacalcidol plus 500 mg calcium per day (group A, n = 43) or 1000 IU vitamin D3 plus 500 mg calcium (group B, n = 42). The two groups were alike in age range, sex ratio, percentages of underlying diseases, average initial bone density values (lumbar spine: mean T-score −3.28 and −3.25, respectively), and rates of vertebral and nonvertebral fractures. During the 3-year study we found a small but significant increase of lumbar spine density in group 1α (+2.0%, P < 0.0001) and no significant changes at the femoral neck. In the D3 group, there were no significant changes at both sites. At the end of the study, 12 new vertebral fractures had occurred in 10 patients of the group 1α and 21 in 17 patients of the D3 group. In accordance with the observed fracture rates, the alfacalcidol group showed a significant decrease in back pain (P < 0.0001) whereas no change was seen in the vitamin D group. We conclude that with the doses used in this trial, alfacalcidol is superior to vitamin D in the treatment of established GIOP.

Efficacy and Safety of Strontium Ranelate in the Treatment of Osteoporosis in Men

CONTEXT Strontium ranelate reduces vertebral and nonvertebral fracture risk in postmenopausal osteoporosis. OBJECTIVE The objective of this study was to determine the efficacy and safety of strontium ranelate in osteoporosis in men over 2 years (main analysis after 1 year). DESIGN This was an international, unbalanced (2:1), double-blind, randomized placebo-controlled trial (MALEO [MALE Osteoporosis]). SETTING This international study included 54 centers in 14 countries. PARTICIPANTS PARTICIPANTS were 261 white men with primary osteoporosis. INTERVENTION Strontium ranelate at 2 g/d (n = 174) or placebo (n = 87) was administered. MAIN OUTCOME MEASURES Lumbar spine (L2-L4), femoral neck, and total hip bone mineral density (BMD), biochemical bone markers, and safety were measured. RESULTS Baseline characteristics were similar in both groups in the whole population (age, 72.9 ± 6.0 years; lumbar spine BMD T-score, -2.7 ± 1.0; femoral neck BMD T-score, -2.3 ± 0.7). Men who received strontium ranelate over 2 years had greater increases in lumbar spine BMD than those who received placebo (relative change from baseline to end, 9.7% ± 7.5% vs 2.0% ± 5.5%; between-group difference estimate (SE), 7.7% (0.9%); 95% confidence interval, 5.9%-9.5%; P < .001). There were also significant between-group differences in relative changes in femoral neck BMD (P < .001) and total hip BMD (P < .001). At the end of treatment, mean levels of serum cross-linked telopeptides of type I collagen, a marker of bone resorption, were increased in both the strontium ranelate group (10.7% ± 58.0%; P = .022) and the placebo group (34.9% ± 65.8%; P < .001). The corresponding mean changes of bone alkaline phosphatase, a marker of bone formation, were 6.4% ± 28.5% (P = .005) and 1.9% ± 25.4% (P = .505), respectively. After 2 years, the blood strontium level (129 ± 66 μmol/L) was similar to that in trials of postmenopausal osteoporosis. Strontium ranelate was generally well tolerated. CONCLUSIONS The effects of strontium ranelate on BMD in osteoporotic men were similar to those in postmenopausal osteoporotic women, supporting its use in the treatment of osteoporosis in men.

Management of osteoporosis in the elderly

ABSTRACT Background: Osteoporosis is predominantly a condition of the elderly, and the median age for hip fracture in women is approximately 83 years. Osteoporotic fracture risk is multifactorial, and often involves the balance between bone strength and propensity for falling. Objective: To present an overview of the available evidence, located primarily by Medline searches up to April, 2009, for the different management strategies aimed at reducing the risk of falls and osteoporotic fractures in the elderly. Results: Frailty is an independent predictor of falls, hip fractures, hospitalisation, disability and death in the elderly that is receiving increasing attention. Non-pharmacological strategies to reduce fall risk can prevent osteoporotic fractures. Exercise programmes, especially those involving high doses of exercise and incorporating balance training, have been shown to be effective. Many older people, especially the very elderly and those living in care institutions, have vitamin D inadequacy. In appropriate patients and given in sufficient doses, vitamin D and calcium supplementation is effective in reducing both falls and osteoporotic fractures, including hip fractures. Specific anti-osteoporosis drugs are underused, even in those most at risk of osteoporotic fracture. The evidence base for the efficacy of most such drugs in the elderly is incomplete, particularly with regard to nonvertebral and hip fractures. The evidence base is perhaps most complete for the relatively recently introduced drug, strontium ranelate. Non-adherence to treatment is a substantial problem, and may be exacerbated by the requirements for safe oral administration of bisphosphonates. Conclusion: Evidence-based strategies are available for reducing osteoporotic fracture risk in the elderly, and include exercise training, vitamin D and calcium supplementation, and use of evidence-based anti-osteoporotic drugs. A positive and determined approach to optimising the use of such strategies could reduce the burden of osteoporotic fractures in this high-risk group.

Therapy of Established Postmenopausal Osteoporosis with Monofluorophosphate plus Calcium: Dose-Related Effects on Bone Density and Fracture Rate

Abstract: Recent experience from different groups suggests that low fluoride doses resulting in moderate increases in bone mineral density (BMD) may be advantageous in terms of fracture-reducing potency. In a randomized prospective 3-year study we examined the therapeutic efficacy of different dosages of monofluorophosphate (MFP) plus calcium in comparison with calcium alone in 134 women with established postmenopausal osteoporosis (mean age 64.0 years, average vertebral fractures per patient 3.6). Group A received 1000 mg calcium/day and a low-dose intermittent MFP regimen (3 months on, 1 month off) corresponding to an average daily fluoride ion dose of 11.2 mg. Group B received 1000 mg calcium/day plus continuous MFP corresponding to 20 mg fluoride ions per day. Group C was treated with 1000 mg calcium alone throughout the study period. Bone density was measured with dual-energy X-ray absorptiometry at L2–4 and three proximal femur areas and with single photon absorptiometry at two radius sites. New vertebral fractures were identified from annual lateral radiographs of the spine. A significant reduction in subjective complaints as measured by a combined pain–mobility score (CPMS) was found in both fluoride groups in comparison with the calcium monotherapy group. Group A showed increases in BMD at all six measuring sites, reaching +12.6% at the spine after 3 years. In group B we found significant increases at the spine, Ward’s triangle and distal radius, but slight decreases at the femoral neck and radius shaft. For the spine the average change amounted to +19.5% after 3 years. In group C losses of BMD were observed at all six sites, with an average loss of 1.6% for the spine at the end of the study. The incidence of new vertebral fractures per 100 patient-years was 8.6, 17.0 and 31.6 in groups A, B and C, respectively. In conclusion, both calcium–MFP regimens resulted in significantly lower vertebral fracture rates than calcium monotherapy. However, the low intermittent MFP regimen, leading to a mean annual increase in spinal BMD of only 4.2%, showed a clear trend to greater effectiveness in reducing vertebral fracture than the higher fluoride dosage that was followed by an average spinal BMD increase of 6.5% per year. Furthermore the rate of fluoride-specific side effects (lower-extremity pain syndrome) was 50% lower in patients receiving the lower fluoride dosage.

Background for studies on the treatment of male osteoporosis: state of the art

Male osteoporosis represents an important, although long underestimated, public health problem. Both in men and in women aging is accompanied by continuous bone loss and by an exponential increase in the incidence of osteoporotic fracture, with a female to male incidence ratio of about 2 to 3 to 1 in the elderly for hip and vertebral fractures. Morbidity after osteoporotic fractures appears to be more serious and mortality more common in men than in women. To date, no single treatment has been proved to be effective and safe in published prospective studies.  The present report, based on a systematic search of the literature on male osteoporosis, summarises the state of the art on the clinical consequences of male osteoporosis and its risk factors, in relation to the present state of knowledge about female osteoporosis. This constitutes the background for the design of rational clinical development strategies for therapeutic interventions in male osteoporosis. From this review of the literature it is apparent that notwithstanding the existing sex differences in pathophysiology of osteoporosis and the difference in age-specific incidence of osteoporotic fractures, there are also important similarities between osteoporosis in women and men. The higher incidence of fracture in women than in men results from quantitative differences in risk factors rather than from different risk factors. Even though there are sex differences in bone geometry, incidence of fracture seems to be similar in men and women for a same absolute areal bone mineral density. However, the lack of data on the changes in fracture rates in men resulting from pharmacological intervention, leading to changes in bone mineral density or bone turnover, remains the main limitation for extrapolation of established treatment outcomes from women to men.

Bone turnover markers and bone mineral density response with risedronate therapy: relationship with fracture risk and patient adherence.

Surrogate markers of fracture risk—bone turnover markers (BTMs) and bone mineral density (BMD)—can be used to monitor treatment response. We assessed whether changes in these markers greater than the least significant change (LSC) were associated with fracture risk reduction and greater adherence. This secondary analysis of the Improving Measurements of Persistence on ACtonel Treatment (IMPACT) study—a multinational prospective, open‐label, cluster‐randomized study of postmenopausal women on oral risedronate 5 mg/d for 52 weeks—assessed adherence by electronic monitors. Urinary N‐terminal cross‐linked telopeptide of type 1 collagen (uNTX) and serum C‐terminal cross‐linked telopeptide of type 1 collagen (sCTX) levels were assessed at baseline and weeks 10 and 22, and BMD at baseline and week 52. Fractures were recorded as adverse events. In 2302 women, responses beyond LSC in BTMs (uNTX and sCTX) and BMD (spine only) were associated with a reduced risk of nonvertebral fractures (NVFs) and all fractures. NVF incidence was about 50% lower in patients with 30% or more of uNTX reduction at week 22 (1.6%) than in those with less than 30% reduction (3.2%, p = .015). NVFs also were reduced in patients with more than 3% spine BMD increase at 52 weeks than those with 3% or less. Responses greater than LSC in BTMs and BMD were associated with greater adherence, but there was no association between adherence and fracture outcomes at 52 weeks. Changes greater than the LSC in BTMs and BMD reflect better treatment adherence, were associated with fracture risk reduction, and identify differences in individual responsiveness to risedronate.

Paget's disease of bone: diagnosis and management.

Summary points Pagets disease is a localised monostotic or polyostotic progressive bone disease of uncertain origin (it may be caused by a slow viral infection) It is characterised by increased bone remodelling, leading to pain, fractures, and deformities with the risk of skeletal, articular, or neurological complications Radiography, scintigraphy, and bone biochemistry are useful tools in achieving a positive diagnosis The primary aim of treatment is to reduce pain and the risk of developing long term complications Potent antiresorptive drugs are now available which control the increased bone remodelling and have led to a dramatic improvement in treatment