Bisphosphonates and osteonecrosis of the jaw

Bisphosphonates are used worldwide as a successful treatment for people with osteoporosis, which is the major underlying cause of fractures in postmenopausal women and older adults. These agents are successful at increasing bone mass and bone trabecular thickness, decreasing the risk of fracture, and decreasing bone pain, enabling individuals to have better quality of life. Bisphosphonates are also used to treat multiple myeloma, bone metastasis, and Paget's disease; however, bisphosphonate treatment may result in negative side effects, including osteonecrosis of the jaw (ONJ). ONJ involves necrotic, exposed bone in the jaw, pain, possible secondary infection, swelling, painful lesions, and various dysesthesias, although less-severe cases may be asymptomatic. First-generation bisphosphonates, which do not contain nitrogen, are metabolized into a nonfunctional, cytotoxic analogue of adenosine triphosphate and cause osteoclast death by starvation. Second-generation bisphosphonates are nitrogen-containing agents; these inhibit osteoclast vesicular trafficking, membrane ruffling, morphology, and cytoskeletal arrangement by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. Physicians treating older adults with osteoporosis and cancer should work together with dental practitioners, pharmacists, and other clinicians to inform individuals receiving bisphosphonates of their possible side effects and to suggest precautionary steps that may minimize the risk of osteonecrosis, particularly of the jaw. These include practicing good oral hygiene; scheduling regular dental examinations and cleanings; and cautioning people who are scheduling treatment for periodontal disease, oral and maxillofacial therapy, endodontics, implant placement, restorative dentistry, and prosthodontics. Recommendations for management of people with ONJ include an oral rinse, such as chlorhexidine, and antibiotics.     

CYP2C8 gene polymorphism and bisphosphonate-related osteonecrosis of the jaw in patients with multiple myeloma

Osteonecrosis of the jaw is an uncommon but potentially serious complication of bisphosphonate therapy in multiple myeloma. Previous studies showed that the presence of one or two minor alleles of the cytochrome P450, subfamily 2C polypeptide 8 gene (CYP2C8) polymorphism rs1934951 was an independent prognostic marker associated with development of osteonecrosis of the jaw in multiple myeloma patients treated with bisphosphonates. The aim of this study was to validate the frequency of SNP rs193451 in 79 patients with multiple myeloma. In 9 (22%) patients developing osteonecrosis of the jaw, a heterozygous genotype was found, in contrast with those who did not develop osteonecrosis of the jaw (n=4, 11%) or healthy individuals (n=6, 13%). We found no differences in the cumulative risk of developing osteonecrosis of the jaw between patients homozygous and heterozygous for the major allele. We were unable to confirm a significant association between this polymorphism and the risk of developing osteonecrosis of the jaw.     

Risedronate once monthly: a potential new regimen for the treatment of postmenopausal osteoporosis

Postmenopausal osteoporosis increases susceptibility to low-trauma fractures due to reduced bone volume and microarchitectural deterioration. Daily nitrogen-containing bisphosphonates have shown antifracture efficacy in many studies and are the most commonly prescribed treatment for women with postmenopausal osteoporosis. However, optimal efficacy is often not achieved due to poor patient adherence to medication. Current dosing schedules are often inconvenient or impractical for patients. Poor adherence increases risk of fracture, which itself increases morbidity, healthcare costs and, potentially, mortality. Although weekly rather than daily dosing of bisphosphonates has improved adherence, significant problems remain. Efforts to reduce dosing frequency as a possible means for further improving adherence (compliance and persistence), and therefore treatment outcomes, are ongoing. Risedronate, a third-generation bisphosphonate, has been shown in multiple clinical trials to reduce fracture risk and improve bone mineral density in postmenopausal women with osteoporosis. Risedronate has a specific structure and set of characteristics that enable less frequent dosing. This paper reviews the structure of risedronate, and how this translates into high antiresorptive potency, favorable bone binding, persistence in bone, and good tolerability that permits less frequent dosing. The paper also reviews the clinical evidence for risedronate, demonstrating the viability of less frequent dosing, with its potential benefits for patient convenience and adherence to therapy. Two equivalence or non-inferiority bridging studies have demonstrated the option of novel risedronate dosing regimens. These studies are reviewed to demonstrate the efficacy and safety of two different monthly regimens of risedronate in the treatment of postmenopausal osteoporosis: 75 mg on 2 consecutive days a month and 150 mg once a month. Data for oral risedronate 150 mg once a month are limited to 1 year’s treatment duration. In previous clinical trials, patients receiving risedronate 5 mg daily have been followed for up to 7 years, with no evidence of loss of effectiveness. Risedronate 150 mg once a month has a comparable efficacy and safety to daily doses in the treatment of postmenopausal osteoporosis. These additional treatment options with risedronate provide easier dosing alternatives for patients.     

Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients

The incidence, characteristics and risk factors for the development of osteonecrosis of the jaw (ONJ) were evaluated among 303 myeloma patients. Only patients who received bisphosphonates developed ONJ (28/254; 11%). Zoledronic acid produced 9.5-fold greater risk for developing ONJ than pamidronate alone (P = 0.042) and 4.5-fold greater risk than subsequent use of pamidronate + zoledronic acid (P = 0.018). Use of thalidomide and number of bisphosphonate infusions also increased the risk for ONJ by 2.4-fold (P = 0.043), and 4.9-fold respectively (P = 0.012). ONJ developed earlier among patients receiving zoledronic acid. Our data indicates that administration of zoledronic acid for more than 2 years or in combination with thalidomide requires caution in myeloma.     

Understanding the mechanisms of senile osteoporosis: new facts for a major geriatric syndrome

Knowledge of the underlying mechanisms of osteoporosis in older adults has significantly advanced in recent years. There is an acute loss of bone mineral density in the peri-menopausal period, followed by a more gradual and progressive decline, which is also seen in men. Markedly increased bone resorption leads to the initial fall in bone mineral density. With increasing age, there is also a significant reduction in bone formation. This is mostly due to a shift from osteoblastogenesis to predominant adipogenesis in the bone marrow. This study reviews new evidence on the pathophysiology of senile osteoporosis, with emphasis upon the mechanism of action of current osteoporosis treatments. New potential treatments are also considered, including therapeutic approaches to osteoporosis in elderly people that focus on the pathophysiology and potential reversal of the adipogenic shift in bone.     

Bisphosphonates in the treatment of osteoporosis

Bisphosphonates are compounds derived from pyrophosphate, a byproduct of cellular cleavage of adenosine triphosphate (ATP), and are resistant to alkaline phosphatase by virtue of replacement of oxygen by carbon. The high affinity of the P-C-P structure for hydroxyapatite accounts for deposition in bone. Modification of the two side chains of carbon alters the potency of the drugs. Of those that have either completed or are undergoing clinical trials, the order of increasing potency for inhibition of bone resorption is etidronate, clodronate, tiludronate, pamidronate, alendronate, residronate and ibandronate (potency range: 1 to 10,000). Less than 5% of bisphosphonates are absorbed and the half life is a few hours. The drugs must be given on an empty stomach because food and beverages interfere with gastrointestinal absorption. Of the absorbed fraction, as much as 60% is taken up by the skeleton and the remainder is excreted un changed in the urine. Etidronate, tiludronate, residronate, and alendronate are given orally, clodronate intravenously, and pamidronate and ibandronate by either route. At lower concentrations, bisphosphonates inhibit osteoclatic bone resorption, whereas at higher concentrations they may inhibit mineralization and cause osteomalacia. Inhibition of mineralization diminishes with increasing potency. In postmenopausal women, etidronate and alendronate for 3 yr were shown to inhibit bone resorption, increase bone mineral density (BMD) of the lumbar spine and hip, and prevent fractures without producing osteomalacia. Bone formation also is reduced as a consequence of diminished bone resorption but reduction is less than the reduction of bone resorption. In higher doses bisphosphonates may cause upper gastrointestinal disturbances but in recommended doses they generally are well tolerated and have an excellent safety profile.     

Osteoporosis in the aging male: Treatment options

In elderly women, loss in bone mass and micro-architectural changes are generally attributed to the onset of menopause. Men do not experience menopause, they do, however, experience age-related acceleration in bone loss and micro-architecture deterioration. The incidence of osteoporotic fractures in elderly men, just as in aged women, increases exponentially with age; the rise in men, however, is some 5–10 years later than in women. Up to 50% of male osteoporotics have no identifiable etiology; however elderly males have much higher likelihood of having an identifiable secondary cause than younger men. Therefore, clinical and laboratory evaluation of aged male osteoporotics must be thorough and should be aimed at identifying lifestyle or conditions contributing to bone loss and fragility. It is essential to identify and treat secondary causes and ensure adequate vitamin D and calcium intake before embarking upon treatment with pharmacological agents. The evidence from a limited number of trials suggests that bisphosphonates, especially alendronate and risedronate, are effective in improving BMD, and seem to be the treatments of choice in aged men with osteoporosis. In cases where bisphosphonates are contra-indicated or ineffective, teriparatide or alternatives such as strontium should be considered.     

Association between Parkinson's disease and low bone density and falls in older men: the osteoporotic fractures in men study

OBJECTIVES: To examine the association between Parkinson's disease (PD) and bone mineral density (BMD) and risk of falls. DESIGN: Cross-sectional and prospective cohort study. SETTING: Six U.S. clinical centers. PARTICIPANTS: Five thousand nine hundred ninety-five community-dwelling, ambulatory men aged 65 and older. MEASUREMENTS: History of physician-diagnosed PD was ascertained from participant self-report. BMD was measured at the hip and spine using dual energy x-ray absorptiometry (DEXA) and quantitative computed tomography (QCT). Incident falls were ascertained for 1 year using mailed queries. RESULTS: Fifty-two participants (0.9%) reported a history of PD. In multivariate models, PD was associated with significantly lower BMD at the spine (-4.9%, P=.04) and total hip (-5.3%, P=.007) using DEXA and at the spine (-6.7%, P=.05) and total hip (-8.2%, P=.03) using QCT. PD was associated with a nearly three times greater age-adjusted risk of multiple future falls (odds ratio (OR)=2.91, 95% confidence interval (CI)=1.55-5.46). Further adjustment for history of multiple falls in the year before baseline attenuated this risk, but it remained significant (OR=2.30, 95% CI=1.15-4.59). CONCLUSION: In this cohort of older men, PD was associated with lower BMD at the hip and spine, measured using areal and volumetric BMD, as well as increased falls. Clinicians should consider screening older men with PD for osteoporosis.     

Comparison of the effects of denosumab with either active vitamin D or native vitamin D on bone mineral density and bone turnover markers in postmenopausal osteoporosis

Osteoporosis is a worldwide health concern. Although treatment with denosumab plus the active vitamin D alfacalcidol has been found to improve femoral neck (FN) and distal forearm bone mineral density (BMD), there have been no reports on the efficacy or adverse effects of denosumab plus eldecalcitol (ELD) in primary osteoporosis patients. Fifty-six treatment-naïve post-menopausal women with primary osteoporosis were recruited and divided into denosumab plus native vitamin D or denosumab plus ELD. Ultimately, 26 subjects in the native vitamin D group and 24 in the ELD group were analyzed. Lumbar and total hip BMD significantly increased in both groups. However, there was no significant difference in the percent increase of lumbar and total hip BMD between two groups. FN-BMD was significantly increased from 6 to 12 months in the ELD group compared with baseline. This study revealed that combination therapy with denosumab and ELD could improve FN-BMD more effectively than denosumab plus native vitamin D. Thus, the addition of ELD may enhance the effects of denosumab treatment for primary osteoporosis.     

A review of postgastrectomy bone disease

Postgastrectomy bone disease was a term devised to describe the metabolic disorders of bone which may follow a gastrectomy operation. Although the use of this operation has declined drastically in recent years, this metabolic bone disorder is still with us and may escape and confuse the unwary. These disorders may take the form of osteomalacia, osteoporosis in excess of normal ageing, or a combination of both. For screening purposes, regular estimations of plasma alkaline phosphatase levels identify patients who may be developing osteomalacia which can then be treated with calcium and vitamin D supplements. Numerically, osteoporosis in excess of ageing is a bigger problem and its prevention and treatment is at present unsatisfactory. Screening procedures for osteoporosis are reviewed, including the more recent methods of bone mineral density assessment. Osteopenia or demineralization occurs in both osteomalacia and osteoporosis therefore osteomalacia must be excluded before attributing any loss to osteoporosis. The present situation with regards to the prevention and treatment of osteoporosis is also reviewed.     

Biochemical, histomorphometric and densitometric changes in patients with multiple myeloma: effects of glucocorticoid therapy and disease activity

It is unknown whether bone changes which can occur in multiple myeloma (MM) are due to cytokine-induced osteoclastic bone resorption from a clone of abnormal plasma cells or high-dose glucocorticoid therapy.
We studied 25 MM patients treated for 1–12 years with combination chemotherapy, subdivided into two groups. Group 1 consisted of 12 patients with stage I and II myeloma and group 2 consisted of 13 patients with stage III MM. Their serum biochemistry, tetracycline-labelled bone histomorphometry and bone densitometry were compared to age- and sex-matched controls.
Patients with MM demonstrated increased indices of bone resorption ( P <0.001 versus controls) and, to a lesser extent, increased indices of bone formation ( P <0.01 versus controls). No patient had evidence of a mineralization defect.
Lumbar spine, femoral neck and total body bone mineral density measurements (BMD) were significantly lower in group 2 compared with group 1 ( P <0.05). Following 12 months of therapy, lumbar spine BMD decreased by 6.6% (95% CI, 2.7% to −9.3%) and femoral neck BMD decreased by 9.5% (95% CI, −3.2% to −15.9%). In a stepwise regression analysis, cumulative prednisolone dosage (B Coef.=−0.39; P =0.03) and plasma cell infiltrate (B Coef.=−0.08; P =0.05) were the most important predictors of lumbar spine bone loss, whereas serum paraprotein (B Coef.=−0.35; P =0.02) and plasma cell infiltrate (B Coef.=−0.20; P =0.04) were the most important predictors of femoral neck bone loss.
We conclude that MM is characterized by high bone turnover with osteoblast–osteoclast uncoupling. Both disease activity and high-dose glucocorticoid therapy may be responsible for the ongoing bone loss seen with MM.     

The clinical utility of bone turnover markers in the evaluation of bone disease in patients with haemophilia A and B

Haemophilia A and B have been associated with increased prevalence of low bone mineral density (BMD). However, the utility of bone turnover markers (BTM) remains unknown. The aim of this study was to evaluate bone metabolism in men with haemophilia and to investigate associations between BTM and bone disease. Serum N‐ (NTX‐I), C‐terminal telopeptide of type I collagen (CTX‐I) and tartrate‐resistant acid phosphatase band‐5b (TRAP‐5b), as bone resorption markers, and osteocalcin (OC) and bone‐specific alkaline phosphatase (b‐ALP), as bone formation markers, were assessed. Seventy men with haemophilia A (n = 59) or B (n = 11) were studied. Patients with low BMD had significantly higher b‐ALP concentrations compared with those with normal BMD (12.8 ± 1.60 vs. 9.72 ± 0.58 μg/L, P = 0.009), without any differences in the other BTM. NTX‐I and CTX‐I concentrations were negatively associated with oestradiol levels and hip BMD and positively with human immunodeficiency virus infection, number of affected joints and arthropathy scores. B‐ALP and OC concentrations were negatively associated with hip BMD, severity of haemophilia and fracture history, and positively with the number of affected joints and testosterone concentrations. After multivariate analysis, NTX‐I levels remained negatively associated with oestradiol levels, whereas b‐ALP concentrations negatively correlated with the level of physical activity and positively with the number of affected joints. Increased bone metabolism exists in men with haemophilia and low BMD. Increased b‐ALP levels may identify patients at high risk for fracture. Increased number of target joints, low physical activity and low oestradiol concentrations are independently associated with increased bone metabolism.     

Longitudinal study of bone mineral density in patients with Crohn's disease

Osteoporosis is frequent in Crohn's disease. The aim of the study was to assess the rate of bone loss over time retrospectively and the influence of disease-related factors on bone loss. Twenty-nine patients (8 male), admitted for repeated bone mineral density assessments (BMD) were enrolled. BMD measured by dual energy x-ray absoptiometry was expressed in grams per square centimeter, and as sex- and age-matched Z score. The mean interval between BMD assessments was 41 months, during which period 27 patients used corticosteroids (mean dose 8.6 g) and 21 patients some form of bone protective medication. Initial Z scores at a mean age of 41 years were significantly below zero (spine –1.6 ± 1.4; femur –1.4 ± 1.4). Over time, no change in absolute BMD was observed accompanied by an improvement in Z scores. At the same time, an increase in body weight and a decrease in erythrocyte sedimentation rate (ESR) was observed. Multilinear regression analysis demonstrated change in ESR as independent predictor for change in femoral Z score. In conclusion, low BMD is frequent in Crohn's disease, but decline of BMD over time was not found, despite ongoing use of corticosteroids.