Retrospective evaluation of serum CTX levels after denosumab discontinuation in patients with or without prior exposure to bisphosphonates.

Discontinuation of denosumab (Dmab) therapy is associated with lower serum CTX levels in osteoporotic patients previously exposed to bisphosphonates compared to those who were not. INTRODUCTION: Discontinuation of Dmab therapy is followed by a transient increase of bone turnover markers (BTMs) above pretreatment values, together with accelerated bone loss, and potentially an increased risk of multiple vertebral fractures. Since a substantial proportion of patients discontinuing Dmab have previously been exposed to bisphosphonates (BPs), we hypothesized that previous BP therapy could attenuate this increase in bone turnover because of the prolonged biological effects of BPs on bone. METHODS: In a retrospective observation, we assessed serum CTX levels between 7 and 24 months after the last Dmab injection in 37 patients (33 women and 4 men, aged 50 to 84 years). CTX levels were analyzed according to the number of Dmab injections (1 or multiple) and previous exposure to BPs. RESULTS: In 8 patients who had received only 1 Dmab injection, 7 out of 8 were previously on BPs and none of them showed CTX values above the premenopausal range after Dmab discontinuation. CTX also remained in the premenopausal range in 14 out of 17 patients who discontinued Dmab after multiple (4.1 ± 1.4, range 2-7) injections but were previously exposed to BPs (mean exposure 6.9 ± 5.8 years, range 11 months-15 years; mean time interval between BP exposure and Dmab initiation 25 ± 10 months, range 0-48). In contrast, in 12 patients who discontinued Dmab after multiple (5, range 3-9) injections without prior exposure to BPs, mean CTX levels as measured on average 11.3 months (range 6-23) after the last Dmab injection were above the upper limit of premenopausal range (mean +114%, range 28-320%, p = 0.003-0.005 vs previous BPs). CONCLUSION: The higher CTX levels occurring after Dmab discontinuation in patients who have received multiple injections may be prevented by prior exposure to BPs. This observation may be related to the persistent effects of BPs on bone that prevent the resorbing activity of newly formed osteoclasts when RANK Ligand is no more antagonized.

Risks and benefits of percutaneous vertebroplasty or kyphoplasty in the management of osteoporotic vertebral fractures.

Vertebral fracture (VF) is the most common osteoporotic fracture and is associated with high morbidity and mortality. Conservative treatment combining antalgic agents and rest is usually recommended for symptomatic VFs. The aim of this paper is to review the randomized controlled trials comparing the efficacy and safety of percutaneous vertebroplasty (VP) and percutaneous balloon kyphoplasty (KP) versus conservative treatment. VP and KP procedures are associated with an acceptable general safety. Although the case series investigating VP/KP have all shown an outstanding analgesic benefit, randomized controlled studies are rare and have yielded contradictory results. In several of these studies, a short-term analgesic benefit was observed, except in the prospective randomized sham-controlled studies. A long-term analgesic and functional benefit has rarely been noted. Several recent studies have shown that both VP and KP are associated with an increased risk of new VFs. These fractures are mostly VFs adjacent to the procedure, and they occur within a shorter time period than VFs in other locations. The main risk factors include the number of preexisting VFs, the number of VPs/KPs performed, age, decreased bone mineral density, and intradiscal cement leakage. It is therefore important to involve the patients to whom VP/KP is being proposed in the decision-making process. It is also essential to rapidly initiate a specific osteoporosis therapy when a VF occurs (ideally a bone anabolic treatment) so as to reduce the risk of fracture. Randomized controlled studies are necessary in order to better define the profile of patients who likely benefit the most from VP/KP.

[Effects of bariatric surgery on bone]. / Conséquences osseuses de la chirurgie bariatrique.

Today, bariatric surgery combines restritive and malabsorptive procedures. Soon after surgery, bone mineral density values assessed by DXA decrease, especially at the hip but the marked weight loss could have some impact on the accuracy of the measurement. In the blood, the values of the biochemical markers of bone resorption and the parathormon are frequently increased. After bariatric surgery, the incidence of fracture is nevertheless not modified as compared to controls.

[Osteoporosis]. / Osteoporose.

Type 2 diadetes is associated with an increased risk of fractures. Calcium supplements are still in the middle of a cardiovascular controversy. Swiss recommandations are available for vitamin D supplementation. Zoledronate exerts a long-term remaining effect on bone resorption. After 5 years treatment with denosumab, fracture incidence remains low. Atypical femoral fractures associated with bisphosphonates treatment have been evaluated in the university hospital of Geneva.

[Osteoporosis in men]. / Osteoporose chez l'homme.

One man out of 5 experiences an osteoporotic fracture in his remaining lifetime at 50 years. Many comorbidities are associated with osteoporosis and fracture risk in men, with numerous associated risk factors beyond a decrease in bone mineral density (BMD), and also taking into account the risk of falling. A prevalent fragility fracture, oral glucocorticoid therapy for at least 3 months, and androgen deprivation therapy for prostate cancer are the three most common situations of increased risk of osteoporosis in men. Bisphosphonates, denosumab and teriparatide increase BMD and change bone turnover markers in the same magnitude as in women. The first anti-fracture data in men were obtained with zoledronic acid and denosumab.

[Teaching about practice guidelines: osteoporosis]. / Enseigner les recommandations pour la pratique: l'ostéoporose.

Family physicians need to know how to teach students practical guidelines for frequent diseases such as osteoporosis. After the age of 50 years, the risk for osteoporotic fractures is 50% for women and 20% for men. It is therefore useful to prevent and screen for osteoporosis. Family physicians need to know how to recognize the clinical and biological risk factors for osteoporosis; they must know when to request a bone densitometry, the "gold standard" for diagnosis. They must also be able to integrate these factors within the clinical context to evaluate the absolute risk of osteoporosis-related fracture that determines the need for specific treatment. Numerous treatments with proven efficacy to reduce global fractures are available but it is important to know their different indications, risk/benefits and potential harmful side-effects.

[Trends in osteoporosis]. / Ostéoporose.

Monoclonal antibody inhibitors against cathepsin-K, Rank-ligand or sclerostin are the therapeutic tools of tomorrow for osteoporosis. Once-a-year infusion, for 3 years, of 5 mg zoledronate reduces the risk of vertebral and hip fractures. 5 mg-infusion of zoledronate in the 90 days following hip fracture, then annual, decreases new clinical fractures and improves survival. 150 mg-risedronate monthly has the same effects than 5 mg daily. Report of osteonecrosis of the jaw associated with bisphosphonate therapy in osteoporosis is low, less than 1/100,000. As raloxifene, basedoxifene reduces the rate of vertebral fractures. Despite its anti-fracture efficacy and safety, strontium ranelate is not available in Switzerland. We need strategies to improve patient's adherence to treatment in osteoporosis.

[Osteoporosis treatment]. / Traitement de l'ostéoporose.

As for any chronic disease, adherence to osteoporosis treatment is low. Folates and vitamin B12 decrease hip fracture risk in elderly Japanese with stroke. Raloxifene (Evista) decreases the incidence of positive estrogen receptor breast cancer and could prevent cardiovascular events in patients at high risk. Strontium ranelate (Protélos) prevents hip fracture in elderly women. The action of alendronate (Fosamax) on bone mineral density and markers of bone remodelling is of higher amplitude than that of risedronate (Actonel). Once monthly ibandronate (Bonviva) increases bone mineral density in post menopausal women with osteoporosis. Excessive suppression of bone remodelling and osteonecrosis of the yaws could be related to bisphosphonate intake.

[Osteoporosis and anti-androgenic therapy in case of prostate cancer]. / Ostéoporose et traitement antiandrogénique du cancer de la prostate.

Anti-androgenic therapy for prostate cancer is associated with an increased risk of osteoporosis and of fracture. A fracture occurence has negative influence on survival. An antiresorptive agent like zoledronate, prevents bone loss consecutive to anti-androgenic therapy.

[Osteoporosis and pain or is osteoporosis painful?]. / Ostéoporose et douteur ou l'ostéoporose fait-elle mal?

Osteoporosis as a disease is characterized by skeletal quantitative and qualitative abnormalities, leading to an increased fragility. Classically the disease is painless. The complications of the disease, that is bone fractures, cause a well-known acute symptomatology. Subsequent chronic pain is the consequence of skeletal deformities, joint incongruences and tensions on musculo-tendineous structures. Pain management includes pharmacological, physio- and ergo-therapeutical measures and stabilisation maneuvers.

[Osteoporosis]. / Ostéoporose.

The diagnosis of osteoporosis is based on the bone mineral density measurement using DXA technology, but the concept of bone quality mainly related to bone architecture is of great interest. The diagnostic threshold of osteoporosis is more and more modulated according to fracture risk factors such as age, prevalent fractures, bone turn-over leading to the definition of a therapeutic threshold. The use of bone resorption inhibitors before or with teriparatide decrease the response of the biochemical markers of bone formation and the gain in bone mineral density. The efficacy of strontium ranelate to decrease vertebral fracture incidence is confirmed and presented on non-vertebral fractures. Bisphosphonates are rapidly effective to prevent fractures and with a long term efficacy. Vitamin D treatment is effective to prevent falls.

Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis.

The aim of this study was to provide confirmation that once-weekly dosing with 70 mg of alendronate (seven times the daily oral dose) and twice-weekly dosing with 35 mg is equivalent to the 10-mg once-daily regimen and to gain more extensive safety experience with this new dosing regimen. Twelve hundred fifty-eight postmenopausal women (aged 42-95 years) with osteoporosis (bone mineral density [BMD] of either lumbar spine or femoral neck at least 2.5 SDs below peak young adult mean or prior vertebral or hip fracture) were assigned to receive oral once-weekly alendronate, 70 mg (n = 519); twice-weekly alendronate, 35 mg (n = 369); or daily alendronate 10 mg (n = 370) for a total of 2 years of double-blind experience. Mean BMD increases from baseline (95% CI) at 24 months in the once-weekly, twice-weekly, and daily treatment groups, respectively, were 6.8% (6.4, 7.3), 7.0% (6.6,7.5), and 7.4% (6.9,7.8) at the lumbar spine and 4.1% (3.8,4.5), 4.3% (3.9,4.7), and 4.3% (3.9,4.7) at the total hip. These increases in BMD as well as the BMD increases at the femoral neck, trochanter, and total body and the reductions of biochemical markers of bone resorption (urinary cross-linked N-telopeptides of type I collagen [NTx]) and bone formation (serum bone-specific alkaline phosphatase [BSAP]) were similar for the three dosing regimens. All treatment regimens were well tolerated with a similar incidence of upper gastrointestinal (GI) adverse experiences. The incidence rates of clinical fractures, captured as adverse experiences, were similar among the groups. The 2-year results confirm the conclusion reached after 1 year that once-weekly alendronate is therapeutically equivalent to daily dosing, providing patients with a more convenient dosing option that may potentially enhance adherence to therapy.

Biochemical markers of bone metabolism in draught and warmblood horses.

Concentrations of the cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and osteocalcin (OC) have been determined in the serum of one hundred clinically healthy adult Draught or Warmblood horses. The correlation between these two markers has been evaluated and the influence of gender, age and type of horse described. No significant variations were observed between animals of different sex, but a significant inverse correlation (P < 0.0001) with age was observed for both measured parameters. After correction for age, serum levels of OC were found to be lower in Draught [adjusted least square mean (LSM) = 6.612 micrograms.L-1] than in Warmblood horses (adjusted LSM = 8.596 micrograms.L-1), whereas levels of ICTP were higher in Draughts (adjusted LSM = 8.035 micrograms.L-1) than in Warmbloods (adjusted LSM = 6.643 micrograms.L-1). A significant correlation (P < 0.0001) was observed between OC and ICTP. This correlation was stronger if the type of horse was taken into account in the statistical model. The ratio OC:ICTP was independent of gender and age. A higher OC:ICTP ratio in Warmbloods compared to the Draught horses might reflect a higher bone remodelling level of horses submitted to regular daily work. It was concluded that ICTP and OC are influenced by the type of horse, and probably reflect a physiological difference in bone remodelling between these animals.

Influence of type and breed of horse on serum osteocalcin concentration, and evaluation of the applicability of a bovine radioimmunoassay and a human immunoradiometric assay [corrected].

OBJECTIVES: To evaluate applicability of a human osteocalcin (OC) immunoradiometric assay (IRMA) for use with equine serum and compare it with a bovine radioimmunoassay (RIA) previously proven valid for such samples, and to describe the effect of type and breed of horses on serum OC concentration. ANIMALS: 100 healthy horses of either sex, classified as type I or II (draught or warmblood, respectively). Each type was represented by 2 breed groups, each comprising 25 horses. PROCEDURE: Blood samples were collected in the morning, and the serum was separated. Osteocalcin was measured, using commercially available RIA and IRMA kits, according to the manufacturer's instructions. All samples were evaluated in duplicate. RESULTS: The human IRMA did not recognize equine OC. Significant variations in the bovine RIA results were observed between types of horses. Draught horses had lower OC concentration, compared with warmblood horses. Significant difference was not observed between breeds for type of horse. Sex had no influence on serum OC values, but age was a significant covariable for both types of horses. CONCLUSIONS: No crossreactivity exists between the equine and human amino- and/or carboxy-terminus of OC, using this particular human IRMA kit. Difference in blood OC concentration exists between draught and warmblood types of horses. CLINICAL RELEVANCE: Use of this human IRMA kit is not valid for equine serum. Horse type must be taken into account when evaluating OC concentration in research or clinical situations, especially if small variations in OC concentration are expected.

Osteoporosis in men.

Osteoporosis in men is becoming a public health problem. The complications of the disease that represent fractures are associated with higher mortality and morbidity in men than in women. In the management of the disease, the nurse plays a major role in the education and management of men with osteoporosis.

Targeted education improves the very low recognition of vertebral fractures and osteoporosis management by general internists.

INTRODUCTION: Vertebral fractures in older persons are strong predictors of subsequent fracture risk but remain largely under-recognized. To evaluate the impact of an educational intervention on the recognition of vertebral fractures and the prescription of anti-osteoporosis treatment among general internists, we conducted a prospective study in a service of general internal medicine of a large university teaching hospital in Geneva, Switzerland. During a 3.5-month observation period (phase 1), all lateral spinal or chest radiographs performed on consecutive inpatients over 60 years were reviewed by two independent investigators, and vertebral fractures were graded according to their severity. METHODS: Results were compared with radiology reports and general internists' discharge summaries. During the following 2-month intervention period (phase 2), internists were actively educated about vertebral fracture identification by means of lectures, posters and flyers. Radiologists did not receive this educational strategy and served as controls. RESULTS: Among 292 consecutive patients (54% men; range: 60-97 years) included in phase 1, 85 (29%) were identified by investigators as having at least one vertebral fracture; radiologists detected 29 (34%), and internists detected 19 (22%). During the intervention phase, 58 (34%) of 172 patients were identified with vertebral fractures by investigators; radiologists detected 13 patients (22%) whereas among internists the detection rate almost doubled (25/58 patients, 43%; p=0.008 compared to phase 1). The percentage of patients with vertebral fracture who benefitted from an osteoporosis medical management increased from 11% (phase 1) to 40% (phase 2, p<0.03). CONCLUSIONS: Our findings confirm the large under-recognition of vertebral fractures, irrespective of their severity, and demonstrate that a simple educational strategy can significantly improve their detection on routine radiographs and, consequently, improve osteoporosis management.

[Prevention and treatment of corticosteroid-induced osteoporosis]. / Prévention et traitement de l'ostéoporose cortico-induite.

Osteoporosis and fractures are frequent and severe consequences of long-term treatment with glucocorticoids. Trabecular bone is mainly affected with a decrease of bone formation and an increase of bone resorption. Prevention and treatment of corticosteroid-induced osteoporosis is based upon general measures such as calcium and vitamin D supplementation, adequate+ protein intake, regular physical exercise, hormonal replacement therapy and upon specific means like therapies used in primary osteoporosis. Bisphosphonates which are potent bone resorption inhibitors have been shown to increase bone mineral density and to decrease fracture rate. Therefore they appear as first choice in the prevention as well as in the treatment of corticosteroid-induced osteoporosis.

Hormone replacement therapy: what is the evidence today?

Based on the most recent studies, it clearly appears that long-term hormone replacement therapy (HRT) prevents fractures but does not improve established coronary artery disease. In addition, HRT leads to a small increase in breast cancer incidence and to a decrease in colorectal cancer incidence. HRT increases the incidence of venous thrombosis, pulmonary embolisms and strokes. As a consequence, HRT can no longer be recommended for primary or secondary prevention of cardiovascular diseases. In addition, it was also demonstrated that HRT was not able to improve cognitive functions and prevent dementia. Therefore regarding daily clinical practice, HRT certainly remains useful to control the symptoms of oestrogen deficiency in recently menopausal patients, but it should definitively no longer be recommended for long-term treatment.

Effect of multiple intravenous pamidronate courses in Paget's disease of bone.

BACKGROUND: Pamidronate is a bisphosphonate whose short-term biological efficacy in Paget's disease of bone was convincingly established many years ago. A less well studied area is the efficacy of pamidronate in slowing disease progression and in preventing and treating complications. MATERIAL AND METHODS: We conducted an uncontrolled retrospective study of 79 Paget's disease patients given multiple intravenous pamidronate courses over a mean period of 45 +/- 19 months. The pamidronate dose per course was 180 mg, usually given over three days. The disease was severe and in some cases had proved refractory to other medications. Reasons for pamidronate therapy were pain or other subjective symptoms; established bone, joint, or nervous system complications; or prevention or these complications in patients with involvement of high-risk sites. RESULTS: Bone and joint pain improved under therapy, and in 78% of cases the outcome in terms of complication treatment and/or prevention was favorable. An important finding was waning of the clinical and biological effects of pamidronate as the number of courses increased. Fourteen percent of patients developed resistance to pamidronate, which seemed more closely related to disease extension than to focal lesion activity. CONCLUSION: These data suggest that a prompt return to normal of laboratory markers, most notably total alkaline phosphatase, should be sought, if needed by using higher doses than in our study.