Osteoporosis and Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD): Back to Basics.

Osteoporosis is defined as a skeletal disorder of compromised bone strength predisposing those affected to an elevated risk of fracture. However, based on bone histology, osteoporosis is only part of a spectrum of skeletal complications that includes osteomalacia and the various forms of renal osteodystrophy of chronic kidney disease-mineral and bone disorder (CKD-MBD). In addition, the label "kidney-induced osteoporosis" has been proposed, even though the changes caused by CKD do not qualify as osteoporosis by the histological diagnosis. It is clear, therefore, that such terminology may not be helpful diagnostically or in making treatment decisions. A new label, "CKD-MBD/osteoporosis" could be a more appropriate term because it brings osteoporosis under the official label of CKD-MBD. Neither laboratory nor noninvasive diagnostic investigations can discriminate osteoporosis from the several forms of renal osteodystrophy. Transiliac crest bone biopsy can make the diagnosis of osteoporosis by exclusion of other kidney-associated bone diseases, but its availability is limited. Recently, a classification of metabolic bone diseases based on bone turnover, from low to high, together with mineralization and bone volume, has been proposed. Therapeutically, no antifracture treatments have been approved by the US Food and Drug Administration for patients with kidney-associated bone disease. Agents that suppress parathyroid hormone (vitamin D analogues and calcimimetics) are used to treat hyperparathyroid bone disease. Antiresorptive and osteoanabolic agents approved for osteoporosis are being used off-label to treat CKD stages 3b-5 in high-risk patients. It has now been suggested that intermittent administration of parathyroid hormone as early as CKD stage 2 could be an effective management strategy. If confirmed in clinical trials, it could mitigate the retention of phosphorus and subsequently the rise in fibroblast growth factor 23 and may be beneficial for coexisting osteoporosis.

Periodontal Disease, Dental Implants, Extractions and Medications Related to Osteonecrosis of the Jaws.

Patients taking bisphosphonates and other anti-resorptive drugs are likely to attend general dental practice. The term 'bisphosphonate'is often immediately associated with osteonecrosis of the jaws (ONJ). Risk assessment and subsequent management of these patients should be carried out taking into account all the risk factors associated with ONJ. The introduction of newer drugs, also shown to be associated with ONJ, demands increased awareness of general dental practitioners about these medications. CPD/CLINICAL RELEVANCE: This paper provides an update on medication-related ONJ and considers the effects of anti-resorptive drugs on the management of patients needing exodontia, treatment for periodontal disease and dental implant placement.

Bisphosphonates and bone quality.

Bisphosphonates (BPs) are bone-avid compounds used as first-line medications for the prevention and treatment of osteoporosis. They are also used in other skeletal pathologies such as Paget's and metastatic bone disease. They effectively reduce osteoclast viability and also activity in the resorptive phase of bone remodelling and help preserve bone micro-architecture, both major determinants of bone strength and ultimately of the susceptibility to fractures. The chemically distinctive structure of each BP used in the clinic determines their unique affinity, distribution/penetration throughout the bone and their individual effects on bone geometry, micro-architecture and composition or what we call 'bone quality'. BPs have no clinically significant anabolic effects. This review will touch upon some of the components of bone quality that could be affected by the administration of BPs.

Safety issues with bisphosphonate therapy for osteoporosis.

Randomized controlled trials have demonstrated the efficacy of bisphosphonates (BP) in improving BMD and reducing fracture risk. Various safety issues that were not noted in clinical trials have, however, now emerged with post-marketing surveillance and increasing clinical experience. The risk of atypical femoral fracture could increase with long-term use of BP, although absolute risk is very small, particularly when balanced against benefits. A drug holiday should be considered after 5 years of treatment for patients at low risk of fracture, although there is no official recommendation regarding this to guide clinicians. Osteonecrosis of the jaw from low-dose BP used for osteoporosis is very rare, and mainly a complication with high-dose i.v. BP used in oncology. The risk of atrial fibrillation too is negligible, and a definite link cannot be established between BP and oesophageal cancer. BP should be avoided in patients with severe renal impairment and during pregnancy and lactation because of limited safety data. Further epidemiological and clinical data are required to establish safety of BP in long-term users (>5 years) and provide evidence-based management.

Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications: cohort analysis using a national prescription database.

Ocular inflammatory reactions have been described in patients on bisphosphonate treatment. We estimated the incidence rate of ocular inflammation at 3 and 12 months in patients treated for osteoporosis using a register-based cohort linked to prescription data (hospitals and private practice) and hospital data. From January 1, 1997 to December 31, 2007, a total of 88,202 patients beginning osteoporosis therapy were identified. Of those patients, 82,404 (93%) began oral bisphosphonates and 5798 (7%) nonbisphosphonates. Within the first year of treatment, 4769 (5.4%) of patients on osteoporosis therapy filled one or more prescriptions for topical eye steroids (TES). TES treatment rates (per 1000 patient-years) in the first year of osteoporosis treatment were 44 (95% confidence interval [CI] 42 to 46) for alendronate, 40 (95% CI 38 to 43) for etidronate, 45 (95% CI 35 to 57) for risedronate, 32 (95% CI 27 to 37) for raloxifene, and 64 (95% CI 49 to 83) for strontium ranelate. After adjustment for age, Charlson index, and the number of comedications, pulmonary disease in men was associated with an increased use of TES (odds ratio [OR] = 1.48; 95% CI 1.17 to 1.86; p = 0.001). In women, malignant disease (OR = 1.27; 95% CI 1.02 to 1.60; p = 0.04) and pulmonary disease (OR = 1.32; 95% CI 1.07 to 1.62; p = 0.01) were significant predictors at 3 months and rheumatic diseases at 12 months (OR = 1.20; 95% CI 1.10 to 1.31; p < 0.001). There was no significant difference between the different drug classes (bisphosphonates versus nonbisphosphonates, alendronate versus nonalendronate-bisphosphonates) for risk of ocular inflammation, with age and the number of comedications being the only significant predictors. Hospital-treated uveitis (48 patients, or 0.05%) showed a similar trend. In conclusion, after initiation of treatment for osteoporosis, the risk of inflammatory eye reactions requiring TES is relatively low and not significantly different between bisphosphonate and nonbisphosphonate users. Patients with a rheumatic or pulmonary disease are at increased risk.

Esophageal and gastric cancer incidence and mortality in alendronate users.

Recent studies have reached conflicting conclusions regarding the risk of esophageal cancer with oral bisphosphonates. Prior studies did not record the number of cancer deaths or endoscopy rates, which could be higher in bisphosphonate users and lead to more cancers being diagnosed at a stage when their esophageal or gastric location could be accurately distinguished. We conducted a register-based, open cohort study using national healthcare data for Denmark. Upper endoscopy frequency, cancer incidence and mortality was examined in 30,606 alendronate users (female, age 50+) and 122,424 matched controls. Primary outcomes were esophageal cancer incidence and death because of esophageal cancer. The analysis showed that alendronate users were more likely to have undergone recent upper endoscopy (4.1 versus 1.7%, p < 0.001). Alendronate users had a lower risk of incident gastric cancer [odds ratio (OR) 0.61; 95% confidence interval (CI): 0.39-0.97) and no increased risk of esophageal cancer (OR 0.71; 95% CI: 0.43-1.19). Risk reductions were greater in users with 10+ prescriptions. The risk of dying of esophageal cancer was significantly reduced in alendronate users after 3 years OR 0.45 (95% CI: 0.22-0.92) but not after 9 years (OR 1.01; 95% CI: 0.52-1.95). An additional comparison with etidronate users revealed no statistically significant difference in outcomes. In conclusion, we found no excess in esophageal cancer deaths or incidence. The early decrease in esophageal cancer rates may relate to the greater use of endoscopy before starting alendronate. Longer term observations also indicated no excess risk of esophageal cancer death and a significantly decreased risk of gastric cancer death.

Safety of bisphosphonates.

Bisphosphonates are one of the most well studied groups of medications and they are bone specific. This tissue specificity is a rare property for a drug introduced into clinical practice as long as 40 years ago. Over the years, the therapeutic boundaries of bisphosphonates were explored and their safety profile has withstood the challenges of the harsh clinical reality and widespread use. Certainly, the esophageal or gastric irritation caused by the oral preparations is an established adverse effect, the risk of which can be reduced by the recommended routine of taking the medication. From the other reported associations with adverse events, osteonecrosis of the jaw (ONJ) and subtrochanteric fractures have attracted most of the attention mainly because their pathophysiology remains unclear. However, overall, only a very small proportion of patients treated with bisphosphonates, especially with the oral formulations, experience adverse events and the overall benefits have consistently outweighed their potential risks. Furthermore, bisphosphonates improve the quality of life in patients with metastatic bone cancer and delay the development of adverse skeletal effects.

Osteonecrosis of the jaw and the role of macrophages.

Nitrogen-containing bisphosphonates have been associated with the development of osteonecrosis of the jaws (ONJ), but the lack of reliable epidemiological data and appropriate animal models has restricted our understanding of ONJ pathophysiology and limited its management. The best available information is from histopathologic findings, which implicate bone necrosis and infection, although it is not clear which is primary. However, there are data suggesting that macrophages could well be the central factor in allowing the infection to develop first, followed by local necrosis, which could also account for the development of ONJ in patients treated with denosumab, a human monoclonal antibody to the receptor activator of nuclear factor-κB ligand. This review examines the evidence that macrophages could play a prominent role in development of ONJ and the proposal that it may be more appropriate to view ONJ as a drug and not only a bisphosphonate-related complication.

Potential therapeutic effects of oral bisphosphonates on the intestine.

Bisphosphonates are the principal drugs prescribed for the prevention of osteoporotic fractures. They are bone specific but poorly absorbed. In oral formulations, almost 99% of the administered dose remains within the intestinal tract and reaches the small and large bowel. Although the nitrogen-containing bisphosphonates can irritate the distal esophageal/gastric mucosa, they improve drug-induced colitis in animal models and exhibit antitumor properties on intestinal cells in vitro. Several recent epidemiological studies provide evidence of a reduced risk of colorectal cancer in osteoporotic patients treated with oral bisphosphonates, notably alendronate. In this review, we will explore the possible mechanisms of action underlying these effects and raise the question of whether these agents might be used in the chemoprophylaxis against colorectal cancer.

Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis.

Bisphosphonates are the leading drugs for the treatment of osteoporosis. In randomized controlled trials (RCTs), alendronate, risedronate, and zoledronate have shown to reduce the risk of vertebral, nonvertebral, and hip fractures, whereas RCTs with ibandronate show antifracture efficacy at vertebral sites. Bisphosphonates are generally well tolerated and safe. Nevertheless, adverse events have been noted, and it is important to consider the strength of the evidence for causal relationships. Effects on the gastrointestinal tract and kidney function are well recognized, as are transient acute-phase reactions. Atrial fibrillation was first identified as a potential adverse event in a zoledronate trial, but subsequent trials and analyses failed to substantiate an association with bisphosphonates. Case reports have suggested a relationship between oral bisphosphonates and esophageal cancer, but this has not been demonstrated in epidemiologic studies. A possible association between bisphosphonate use and osteonecrosis of the jaw (ONJ) has also been suggested. However, the risk of ONJ in patients with osteoporosis appears to be very low, with no evidence from prospective RCTs of a causal association. There are reports of occasional occurrence of subtrochanteric or diaphyseal fractures in osteoporotic patients, but an association with bisphosphonate therapy is not substantiated by epidemiologic studies or prospective RCTs.

A review of the literature on osteonecrosis of the jaw in patients with osteoporosis treated with oral bisphosphonates: prevalence, risk factors, and clinical characteristics.

OBJECTIVE: This literature review was performed to elucidate the relationship between bisphosphonate use and development of osteonecrosis of the jaw (ONJ) in patients receiving oral bisphosphonates for the treatment of osteoporosis. METHODS: MEDLINE, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and EMBASE were searched for English-language articles published from 1966 to September 2006 whose titles included the term osteonecrosis of the jaw in conjunction with bisphosphonates, alendronate, risedronate, ibandronate, etidronate, clodronate, zoledronic acid, or pamidronate. Articles were included in the review if the population consisted of adults with ONJ; patients received bisphosphonates for the treatment of osteoporosis only; the reported data included baseline characteristics of the study population (age; sex; comorbidities; concomitant medications; history of dental surgery, trauma, or infection), characteristics of bisphosphonate treatment (specific bisphosphonate, dose, duration of treatment, mode of administration), clinical features of ONJ (signs, symptoms, site), the treatment protocol used to manage ONJ, or the prevalence of ONJ in patients with osteoporosis treated with bisphosphonates; and the publication involved a case report, case series, or observational study. RESULTS: After application of the search strategy and the inclusion/exclusion criteria, 11 publications reporting 26 cases of ONJ in patients receiving bisphosphonates for the treatment of osteoporosis were included in the review. The most commonly affected site was the mandible (16 patients), followed by the maxilla (6 patients). Among the 23 patients whose age was reported, 18 (78%) were aged >or=60 years. Among the 23 patients whose sex was reported, only 3 (13%) were men. Of 15 patients with a history of invasive dental treatment, 12 (80%) had undergone dental surgery or experienced dental trauma at the site of ONJ. Among the 10 patients for whom the duration of bisphosphonate treatment was reported, no clear relationship between the duration of bisphosphonate treatment and the development of ONJ was observed. CONCLUSIONS: Considering that millions of patients have been prescribed bisphosphonates for the treatment of osteoporosis, the relative prevalence of ONJ in these patients was low. Age >or=60 years, female sex, and previous invasive dental treatment were the most common characteristics of those who developed ONJ. However, it is not possible to draw further conclusions about the potential association between oral bisphosphonate use and ONJ in the identified studies because of incomplete reporting and the presence of confounding factors.

Systemic inflammatory mediators and bone homeostasis in intestinal failure.

BACKGROUND: A proinflammatory state has been described in patients with intestinal failure. The prevalence of metabolic bone disease in this group is considerable. It is not known whether this proinflammatory state is related to bone parameters, though bone disease is recognized as a proinflammatory process in postmenopausal women. The purpose of this study was to examine whether inflammation was related to bone disease. METHODS: Eight patients with parenteral nutrition (PN)-dependent intestinal failure but no recent infections or immunosuppressive medications had serum assayed for interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, and its receptors (TNFR-I and TNFR-II), C-reactive protein, and whole blood for lymphocyte proliferation. Routine clinical laboratory measures of vitamin D, parathyroid hormone, serum calcium, and phosphorus within 3 months of the inflammatory measures were compared by Pearson's correlation to the inflammatory measures. RESULTS: Mean values for calcium, phosphorus, and albumin were normal, but 25-hydroxy vitamin D was reduced and parathyroid hormone and alkaline phosphatase elevated. Serum total calcium was negatively related to TNFR-II, TNF-alpha and positively to T-helper cells. Longer PN dependence was associated with inflammation and negatively with T-helper cells. CONCLUSIONS: These preliminary findings are hypothesis generating only but support an association of low calcium and longer duration of PN with inflammation in patients with intestinal failure. Whether the inflammation results from vitamin D deficiency or the vitamin D deficiency develops secondary to excessive use of activated vitamin D to modulate inflammation from some other cause, such as a component of PN or repeated infectious challenge, requires further study.