The doubled burden of diabetic bone disease: hip fracture and post-hip fracture mortality.

OBJECTIVE: Patients with diabetes have an increased risk of osteoporosis and shorter life expectancy. Hip fracture (HF) is the most serious consequence of osteoporosis and is associated with increased mortality risk. We aimed to assess the association of antidiabetic medications with HF and the post-hip fracture mortality risk among diabetic patients ≥50 years. DESIGN: In this nationwide case-control study 53 992 HF cases and 112 144 age-, sex- and region-matched non-hip fracture controls were analyzed. A cohort of hip-fractured diabetic patients were followed-up for an all-cause mortality. METHODS: We defined three groups of diabetic patients based on a prescription of antidiabetic medications: group 1 treated with insulin monotherapy (G1DM), group 2 (G2DM) treated with blood glucose-lowering drugs (BGLD) only, group 3 on a combined BGLD and insulin therapy (G3DM). We applied logistic regression and Cox regression. RESULTS: We identified 2757 G1DM patients, 15 310 G2DM patients, 3775 G3DM patients and 144 294 patients without any antidiabetic treatment. All three groups of diabetic patients had increased odds of HF compared to controls. G1DM patients aged 50-64 years (aOR: 4.80, 95% CI: 3.22-7.17) and G3DM patients (aOR: 1.39, 95% CI: 1.02-1.88) showed the highest HF odds, whereas G2DM patients had 18% decrease in HF odds than their non-diabetic controls (aOR: 0.82, 95% CI: 0.69-0.99). All diabetic patients had increased post-hip fracture mortality risk compared to non-diabetic controls. The highest mortality hazard was observed in G1DM patients, being greater for women than men (HR: 1.71, 95% CI: 1.55-1.89 and HR: 1.44, 95% CI: 1.27-1.64, respectively). CONCLUSIONS: Antidiabetic medications increase the probability of HF. Diabetic patients, who sustained HF have a higher mortality risk than non-diabetic patients.

A critical assessment of the potential of pharmacological modulation of aldehyde dehydrogenases to treat the diseases of bone loss.

Chronic alcoholism (CA) decreases bone mass and increases the risk of hip fracture. Alcohol and its main metabolite, acetaldehyde impairs osteoblastogenesis by increasing oxidative stress. Aldehyde dehydrogenase (ALDH) is the rate-limiting enzyme in clearing acetaldehyde from the body. The clinical relevance of ALDH in skeletal function has been established by the discovery of single nucleotide polymorphism, SNP (rs671) in the ALDH2 gene giving rise to an inactive form of the enzyme (ALDH2*2) that causes increased serum acetaldehyde and osteoporosis in the affected individuals. Subsequent mouse genetics studies have replicated human phenotype in mice and confirmed the non-redundant role of ALDH2 in bone homeostasis. The activity of ALDH2 is amenable to pharmacological modulation. ALDH2 inhibition by disulfiram (DSF) and activation by alda-1 cause reduction and induction of bone formation, respectively. DSF also inhibits peak bone mass accrual in growing rats. On the other hand, DSF showed an anti-osteoclastogenic effect and protected mice from alcohol-induced osteopenia by inhibiting ALDH1a1 in bone marrow monocytes. Besides DSF, there are several classes of ALDH inhibitors with disparate skeletal effects. Alda-1, the ALDH2 activator induced osteoblast differentiation by increasing bone morphogenic protein 2 (BMP2) expression via ALDH2 activation. Alda-1 also restored ovariectomy-induced bone loss. The scope of structure-activity based studies with ALDH2 and the alda-1-like molecule could lead to the discovery of novel osteoanabolic molecules. This review will critically discuss the molecular mechanism of the ethanol and its principal metabolite, acetaldehyde in the context of ALDH2 in bone cells, and skeletal homeostasis.

A cost-effectiveness analysis of denosumab for the prevention of skeletal-related events in patients with multiple myeloma in four European countries: Austria, Belgium, Greece, and Italy.

Aim: The approved indication for denosumab (120 mg) was expanded in 2018 to include skeletal-related event (SRE) prevention in patients with multiple myeloma (MM). Therefore, a cost-effectiveness analysis was conducted comparing denosumab with zoledronic acid (ZA) for SRE prevention in patients with MM from the national healthcare system perspective in a representative sample of European countries: Austria, Belgium, Greece, and Italy. Methods: The XGEVA global economic model for patients with MM was used to calculate incremental cost-effectiveness ratios (ICERs) for denosumab vs ZA over a lifetime horizon. Clinical inputs were derived from the denosumab vs ZA randomized, phase 3 study ("20090482") in patients newly-diagnosed with MM, and comprised real-world adjusted SRE rates, serious adverse event (SAE) rates, treatment duration, dose intensity, progression-free survival (PFS), and overall survival (OS). Economic inputs comprised country-specific denosumab and ZA acquisition and administration costs, SRE and SAE management costs, and discount rates. Health utility decrements associated with MM disease progression, SRE and SAE occurrence, and route of administration were included. Results: Estimated ICERs (cost per quality-adjusted life-year [QALY] gained) for denosumab vs ZA in Austria, Belgium, Greece, and Italy were €26,294, €17,737, €6,982, and €27,228, respectively. Using 1-3 times gross domestic product (GDP) per capita per QALY as willingness to pay thresholds, denosumab was 69-94%, 84-96%, 79-96%, and 50-92% likely to be cost-effective vs ZA, respectively. Limitations: Economic inputs were derived from various sources, and time to event inputs were extrapolated from 20090482 study data. Conclusions: Denosumab is cost-effective vs ZA for SRE prevention in patients with MM in Austria, Belgium, Greece, and Italy, based on often-adopted World Health Organization thresholds. This conclusion is robust to changes in model parameters and assumptions. Cost-effectiveness estimates varied across the four countries, reflecting differences in healthcare costs and national economic evaluation guidelines.

Pegfilgrastim-Induced Bone Pain: A Review on Incidence, Risk Factors, and Evidence-Based Management.

OBJECTIVE: To review the incidence, risk factors, and management of pegfilgrastim-induced bone pain (PIBP). DATA SOURCES: PubMed was searched from 1980 to March 31, 2017, using the terms pegfilgrastim and bone pain. STUDY SELECTION AND DATA EXTRACTION: English-language, human studies and reviews assessing the incidence, risk factors, and management of PIBP were incorporated. DATA SYNTHESIS: A total of 3 randomized, prospective studies and 2 retrospective studies evaluated pharmacological management of PIBP. Naproxen compared with placebo demonstrated a reduction in the degree, incidence, and duration of bone pain secondary to pegfilgrastim. Loratadine was not effective in reducing the incidence of bone pain prophylactically, but a retrospective study evaluating dual antihistamine blockade with loratadine and famotidine demonstrated a decreased incidence in bone pain when administered before pegfilgrastim. CONCLUSION: Naproxen is effective at managing PIBP. Although commonly used, antihistamines have a paucity of data supporting their use. Dose reductions of pegfilgrastim and opioids may also be potential management options; however, data supporting these treatment modalities are scarce.

Use of dual-energy X-ray absorptiometry (DXA) for diagnosis and fracture risk assessment; WHO-criteria, T- and Z-score, and reference databases.

Dual-energy X-ray absorptiometry (DXA) is a two-dimensional imaging technology developed to assess bone mineral density (BMD) of the entire human skeleton and also specifically of skeletal sites known to be most vulnerable to fracture. In order to simplify interpretation of BMD measurement results and allow comparability among different DXA-devices, the T-score concept was introduced. This concept involves an individual's BMD which is then compared with the mean value of a young healthy reference population, with the difference expressed as a standard deviation (SD). Since the early nineties of the past century, the diagnostic categories "normal, osteopenia, and osteoporosis", as recommended by a WHO working Group, are based on this concept. Thus, DXA is still the globally accepted "gold-standard" method for the noninvasive diagnosis of osteoporosis. Another score obtained from DXA measurement, termed Z-score, describes the number of SDs by which the BMD in an individual differs from the mean value expected for age and sex. Although not intended for diagnosis of osteoporosis in adults, it nevertheless provides information about an individual's fracture risk compared to peers. DXA measurement can either be used as a "stand-alone" means in the assessment of an individual's fracture risk, or incorporated into one of the available fracture risk assessment tools such as FRAX® or Garvan, thus improving the predictive power of such tools. The issue which reference databases should be used by DXA-device manufacturers for T-score reference standards has been recently addressed by an expert group, who recommended use National Health and Nutrition Examination Survey III (NHANES III) databases for the hip reference standard but own databases for the lumbar spine. Furthermore, in men it is recommended use female reference databases for calculation of the T-score and use male reference databases for calculation of Z-score.

Central skeletal sarcoidosis: a case report with sustained remission only on methotrexate, and a literature review on the imaging approach, treatment, and assessment of disease activity.

We report a case of multifocal involvement of the central skeleton in a patient with long-term stage I pulmonary sarcoidosis who experienced sustained clinical remission of musculoskeletal symptoms while on methotrexate (MTX) alone. Concomitant normalization of laboratory tests [inflammatory markers and angiotensin-converting enzyme (ACE) levels] was observed, and improvements were seen in follow-up magnetic resonance imaging (MRI) of the lumbar spine and bone scintigraphy. To date, there are no specific tools for the assessment of skeletal disease activity in sarcoidosis. Our case suggests that inflammatory markers and ACE levels, when initially elevated, bone scintigraphy, and-in the case of vertebral involvement-MRI could serve as such tools. A literature review on the imaging approach, treatment, and disease activity monitoring of skeletal sarcoidosis is also provided.

Incidence of serious side effects with intravenous bisphosphonate: a clinical audit.

BACKGROUND: Bisphosphonates (BP) have been associated with osteonecrosis of the jaw (ONJ) and atypical femoral fractures (AFF). The prevalence of these side effects in intravenous (IV) BP-treated subjects is not well understood. AIM: This audit aimed to delineate the prevalence of ONJ, thigh pain and AFF in patients having regular IV BP and its effect on bone mineral density (BMD). Design and METHODS: Patients attending for IV BP over a 3-month period completed a questionnaire about thigh pain and dental health. Data concerning BMD, treatment indication and treatment history were obtained from medical records. RESULTS: There were 201 patients between 28 and 94 years (74.1% female) mostly on zoledronate (ZOL) (102) or pamidronate (PAM) (97). Osteoporosis (75.6%) and Paget's disease (16.5%) were the main indications for treatment; median length of IV BP was 4 years (range 0.25-25). One patient had ONJ (0.5%) while oral pain was reported by 6.5% and 12.7% noted tooth loosening. Twenty-seven subjects (13.4%) complained of current thigh pain. AFF occurred in four patients (2%), none of whom had idiopathic osteoporosis. At time of AFF, only one patient had a femoral neck T-score less than -2.5. All four had received pamidronate treatment; median 12.5 years (range 7-22). IV BP treatment significantly increased lumbar spine BMD but not femoral neck BMD. CONCLUSION: Classical ONJ was rare (0.5%), although tooth loss was more frequent. Thigh pain was frequent while AFF occurred in 2.0% of subjects and was associated with long treatment periods and non-osteoporotic bone.

Pharmacoeconomics of bisphosphonates for skeletal-related event prevention in metastatic non-breast solid tumours.

Bisphosphonates reduce the risk of skeletal-related events (SREs; i.e. spinal cord compression, pathological fracture, radiation or surgery to the bone, and hypercalcaemia) in patients with metastatic cancer. A number of analyses have been conducted to assess the cost effectiveness of bisphosphonates in patients with bone metastases secondary to breast cancer, but few in other solid tumours. This is a review of cost-effectiveness analyses in patients with non-breast solid tumours and bone metastases. A literature search was conducted to identify cost-effectiveness analyses reporting the cost per QALY gained of bisphosphonates in patients with metastatic bone disease secondary to non-breast solid tumours. Four analyses met inclusion criteria. These included two in prostate cancer (one of which used a global perspective but expressed results in $US, and the other reported from a multiple country perspective: France, Germany, Portugal and the Netherlands). The remaining analyses were in lung cancer (in the UK, France, Germany, Portugal and the Netherlands), and renal cell carcinoma (in the UK, France and Germany). In each analysis, the cost effectiveness of zoledronic acid versus placebo was analysed. Zoledronic acid was found to be cost effective in all European countries across all three indications but not in the sole global prostate cancer analysis. Across countries and indications, assumptions regarding patient survival, drug cost and baseline utility (i.e. patient utility with metastatic disease but without an SRE) were the most robust drivers of modelled estimates. Assumptions of SRE-related costs were most often the second strongest cost driver. Further review indicated that particular attention should be paid to the inclusion or exclusion of nonsignificant survival benefits, whether health state utilities were elicited from community or patient samples or author assumptions, delineation between symptomatic and asymptomatic SREs, and the methods with which SRE disutility was modelled over time. While the field of cost-effectiveness analysis in solid tumours other than breast cancer is still evolving, outcomes will likely continue to be driven by drug cost and assumptions regarding treatment benefits. Although considerations such as adverse events and administration costs are important, they were not found to influence cost-effectiveness estimates greatly. As zoledronic acid will lose patent protection in 2013 and subsequently be greatly reduced in price, it is likely that the field of cost effectiveness will change with regard to SRE-limiting agents. Meanwhile, research should be conducted to improve our understanding of the impact on quality of life and medical costs of preventing SREs.

[Bisphosphonate treatment of osteoporosis and other skeletal diseases]. / Bisfosfonatbehandling av osteoporose og andre skjelettsykdommer.

BACKGROUND: Bisphosphonates are antiresorptive drugs widely used to treat osteoporosis. They are also used to treat hereditary skeletal diseases with systemic or local defects, and as a supplement in treatment of cancer. This paper provides an overview of pharmacokinetics, mode of action, and clinical effects. MATERIAL AND METHODS: Literature was retrieved through a non-systematic search in Pubmed/Medline. RESULTS: Bisphosphonates are derivates of pyrophosphate which bind to hydroxyapatite with high affinity. Aminobisphosphonates inhibit an enzyme in the mevalonate pathway, thereby inducing apoptosis and inhibiting osteoclast activity. A reduced incidence of vertebral and hip fractures has been shown for alendronate, risedronate and zoledronate, while ibandronate has been shown to only reduce vertebral fracture. Reduced mortality was observed in a study where patients with recent hip fracture were treated with zoledronic acid. Intravenous bisphosphonates improve compliance and are relatively simple to use. Bisphosphonates reduce the risk for skeletal complications and bone pain in breast cancer, myelomatosis and prostate cancer. They are also effective in the treatment of Paget's disease and bone marrow edema. Gastrointestinal adverse effects are relatively frequent with peroral bisphosphonates, while acute phase reactions with influenza-like symptoms are common with intravenous bisphosphonates. INTERPRETATION: Aminobisphoshonates are effective in the treatment of osteoporosis and in other bone diseases, and as an adjuvance in the treatment of cancer.

Management of bisphosphonate treatment in clinical practice.

Bisphosphonates have become important tools for the treatment of bone lesions from various solid tumors or from multiple myeloma. Management of bone health in patients with malignant bone disease from breast cancer, prostate cancer, lung cancer, and multiple myeloma was discussed in clinical case workshops held during the ZENITH meeting (April 2007, Prague, Czech Republic). Physicians in attendance were generally in agreement that bisphosphonate therapy is recommended for treatment of bone metastases and that treatment should be sustained over the duration of disease progression. Consensus is still evolving regarding the optimal duration of therapy and the emerging role of bisphosphonates in the management of bone loss in the adjuvant setting. Bisphosphonates have proven efficacy in reducing and delaying skeletal-related events in patients with bone metastases, and play a key role in preserving patient functional independence and quality of life. Furthermore, bisphosphonate therapy is a cost-effective strategy in the care of patients with bone metastases compared with the cost of treatment for fractures and other skeletal complications. Finally, communication with patients is critical to increase awareness of the benefits of bisphosphonate therapy. Increased patient involvement with treatment decisions will likely encourage patient compliance and thereby maximize clinical benefit from bisphosphonate therapy.

Combination ibandronate and radiotherapy for the treatment of bone metastases: clinical evaluation and radiologic assessment.

PURPOSE: Ibandronate is a single-nitrogen, noncyclic bisphosphonate with proven efficacy for reducing metastatic bone pain. In this study, we assessed the palliative effects of combined ibandronate and radiotherapy. METHODS AND MATERIALS: Forty-five patients with bone metastases from various solid tumors received external-beam radiotherapy, 30-40 Gy over 3-4.5, weeks combined with 10 cycles of monthly intravenous ibandronate, 6 mg. RESULTS: After combined therapy, mean bone pain scores (graded from 0 to 10) were reduced from 6.3 at baseline to 0.8 after 3 months, with further reductions at later time points (all p < 0.001). Opioid use decreased from 84% of patients at baseline (38/45) to 24% (11/45) at 3 months, with further subsequent reductions (all p < 0.001). Mean performance status and functioning scores also significantly improved. Bone density (assessed by computed tomography scan) increased by 20% vs. baseline at 3 months, 46% at 6 months, and 73% at 10 months (all p < 0.001). Lesion improvement was also demonstrated by magnetic resonance imaging. Treatment was well tolerated with no renal toxicity. CONCLUSIONS: In this pilot study, combined radiotherapy and ibandronate provided substantial bone pain relief and increased bone density. Computed tomography-based or magnetic resonance imaging-based evaluations offer objective methods for assessing therapeutic outcomes.

Myeloma bone disease: pathogenetic mechanisms and clinical assessment.

Bone disease in multiple myeloma (MM) leads to progressive devastation of the skeleton and is the most severe cause of morbidity. Its pathogenetic mechanisms are not fully defined, though the current evidence points to hyperactivation of osteoclasts (OC) in presence of a major defect of bone repairing in erosion sites due to osteoblast (OB) impairment. Bone resorption, however, is promoted by early OB, namely stromal cells that respond to chronic stimulation by myeloma cells by enhancing marrow levels of RANKL and other osteoclastogenic factors and thus accelerating the maturation of OC progenitors. In myeloma bone disease (MBD), OBs are systematically defeated by a number of inhibiting effects induced by the malignant clone within the marrow microenvironment. Thus, MBD primarily affects the OB lineage, particularly in overt MM, where serum markers of osteoblastogenesis, such as osteocalcin and osteoprotegerin, are extremely low in contrast with their slight increase in inactive MM. These markers, in association with others of bone turnover (RANKL, MIP-1alpha, type I collagen telopeptides such as NTX and CTX) may be used in the clinical assessment of MBD as well as to monitor the efficacy of bisphosphonate in delaying the progressive skeletal destruction.

Clodronate.

Clodronate is a second-generation bisphosphonate of intermediate potency between etidronate and aminobisphosphonates. It is an effective inhibitor of bone resorption, but unlike etidronate does not impair the mineralization of bone. Unlike pamidronate, it can be given both intravenously and orally. There is wide experience in the use of clodronate in the management of patients of hypercalcemia. The most widely used therapeutic regimen is 300 mg intravenously repeated for 5 days or a single infusion of 1500 mg. Efficacy is nearly complete in patients with myelomatosis, less complete in solid tumors with hypercalcemia but without skeletal metastases, and intermediate in patients with solid tumors in the presence of skeletal metastases. Variations in effect appear to be due to differences in renal tubular reabsorption of calcium between the three disorders. Placebo-controlled studies examining the effects of clodronate on bone pain in the absence of hypercalcemia have shown significant decreases in the severity of bone pain. These findings, coupled with the knowledge that suppression of bone resorption persists for the duration of treatment, has led to the long term use of oral doses of clodronate to decrease the incidence of complications of osteolytic bone disease. The long term control of bone resorption with oral clodronate has been demonstrated by double blind histologic studies. The ultimate arbiter of the value of clodronate is whether it decreases the skeletal morbidity associated with osteolysis. Double blind prospective controlled studies suggest that the incidence of bone pain, fracture, and hypercalcemia can be decreased significantly in patients with breast carcinoma. In addition, the use of long term clodronate in patients with myelomatosis significantly decreases the progression of osteolytic bone lesions, the risk of fractures, and the incidence of hypercalcemia. These studies have raised the possibility that bone disease might be prevented in individuals at high risk. Double blind prospective studies in women with recurrent breast carcinoma but no evidence of skeletal metastases showed a small effect of clodronate in decreasing the proportion of women developing metastatic disease. However, there was a large and significant decrease in the number of skeletal metastases associated with a decrease in skeletal morbidity. These observations suggest that clodronate may modify the natural history of the expression of skeletal disease, and thereby significantly improve the quality of life of affected patients.

Ceftriaxone therapy of bone and soft tissue infections in hospital and outpatient settings.

Ceftriaxone, a broad-spectrum cephalosporin with a markedly extended half-life, was administered to 100 patients with 56 bone and 44 soft tissue infections. Sixty-eight received 1 g twice daily, and 32 received 2 g once daily intravenously. Overall, 91% had a satisfactory clinical response, with similar efficacies in both treatment regimens. In six patients, failure to achieve a cure correlated well with the development of resistance to ceftriaxone during therapy in Enterobacter and Pseudomonas species (two cases) and with superinfection with Bacteroides fragilis (four cases). In 41 patients, intravenous drug therapy was continued after discharge from the hospital. In this group, 1,093 patient-days of hospitalization were saved, amounting to $150,020 in cost savings. The prolonged half-life facilitated the administration of ceftriaxone in this setting.

Renal osteopenia - an assessment of long-term therapy with vitamin D analogues.

Renal bone disease was assessed for an average of 5.5 years in 9 patients on maintenance haemodialysis. The investigative methods included serial biochemical estimations, radiographic skeletal surveys and quantitative bone histology. Repeated bone mineral analyses and neutron activation analyses of a hand were also performed in order to monitor changes in skeletal calcium content. Before treatment, progressive osteodystrophy was demonstrated by all techniques. Following therapy with the vitamin D analogues, all patients noted symptomatic improvement; serum alkaline phosphatase reverted to normal and serum parathyroid hormone concentrations decreased. Radiographically, subperiosteal erosions healed while the histological features of osteomalacia and osteitis fibrosa were abolished. Both bone mineral and neutron activation analyses indicated that progressive skeletal demineralisation had been halted. However, a sustained increase in the overall mineral content of bone was not demonstrated. Thus, vitamin D therapy although improving the biochemical, radiological, and histological features of renal osteodystrophy may not restore bone mass to osteopenic bone.

Intravenous antibiotic therapy at home.

During a 12-month period, 23 patients aged 12 to 78 years were treated for 8 to 40 days (mean, 23 days) at home with intravenous (i.v.) antibiotics. Diseases treated included bone and joint infection (14 patients), blastomycosis (two), actinomycosis (two), staphylococcal bacteremia (two), endocarditis (two), and candidal pyelonephritis (one). After initial in-hospital training, patients self-administered their drugs through a heparin-lock i.v. cannula, which was changed regularly by a visiting home care nurse. Antibiotics administered included cloxacillin, penicillin G, cephalosporins, gentamicin, carbenicillin, and amphotericin B. Patient and family acceptance of the program was good, the program was therapeutically effective, and, apart from a decreased prevalence of phlebitis with the heparin lock at home, side effects were no different from those of in-hospital-treated patients. The cost of home therapy was $ 40 per patient-day compared with an estimated $ 137 had the patients remained in hospital. Most patients were able to resume normal activities while receiving home i.v. therapy.

The use of salsalate for control of long-term musculo-skeletal pain: an open, non-comparative assessment.

An open study was carried out in general practice to assess the analgesic effectiveness, tolerance and side-effects of salsalate when given at a dosage of 3 g per day for 6 weeks. Sixty-six patients who were known long-term analgesic users were treated: they included 16 with active inflammatory disease of rheumatoid type, 20 with degenerative joint disease, and 27 with other musculo-skeletal conditions. Three patients were withdrawn during the study because of gastro-intestinal upset. Assessments, using rating scale scores, were made pre-trial and at 2-weekly intervals of joint pain, other musculo-skeletal pain, and duration of morning stiffness. The results showed that there was marked improvement in joint pain and morning stiffness, particularly in those patients with inflammatory joint disease. Improvement in musculo-skeletal discomfort was less evident. Side-effects were reported on 24 occasions, the most frequent being dyspepsia. Faecal occult blood tests showed that there were 7 patients with probable blood loss during treatment, 4 of them, however, had no other clinical signs or symptoms of gastrointestinal intolerance.

A long-term assessment of flurbiprofen.

A multi-centre open study of flurbiprofen was started in 1971 to provide regular clinical and laboratory data on patients with a variety of arthritic conditions. To date, 1220 patients have received the drug in a dosage varying from 75 mg to 400 mg daily. Flurbiprofen has been shown to be effective in relieving symptoms in the degenerative and inflammatory arthritides and side-effects have not proved a problem. Patients aged 65 years and over appear to tolerate the drug as well as their younger counterparts, an important finding in a group of patients notoriously intolerant of many drugs.