Elizabeth Shane

Bisphosphonate-Associated Osteonecrosis of the Jaw: Report of a Task Force of the American Society for Bone and Mineral Research

ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Report of a Task Force of the American Society for Bone and Mineral Research

Bisphosphonates (BPs) and denosumab reduce the risk of spine and nonspine fractures. Atypical femur fractures (AFFs) located in the subtrochanteric region and diaphysis of the femur have been reported in patients taking BPs and in patients on denosumab, but they also occur in patients with no exposure to these drugs. In this report, we review studies on the epidemiology, pathogenesis, and medical management of AFFs, published since 2010. This newer evidence suggests that AFFs are stress or insufficiency fractures. The original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution. The periosteal stress reaction at the fracture site was changed from a minor to a major feature. The association with specific diseases and drug exposures was removed from the minor features, because it was considered that these associations should be sought rather than be included in the case definition. Studies with radiographic review consistently report significant associations between AFFs and BP use, although the strength of associations and magnitude of effect vary. Although the relative risk of patients with AFFs taking BPs is high, the absolute risk of AFFs in patients on BPs is low, ranging from 3.2 to 50 cases per 100,000 person‐years. However, long‐term use may be associated with higher risk (∼100 per 100,000 person‐years). BPs localize in areas that are developing stress fractures; suppression of targeted intracortical remodeling at the site of an AFF could impair the processes by which stress fractures normally heal. When BPs are stopped, risk of an AFF may decline. Lower limb geometry and Asian ethnicity may contribute to the risk of AFFs. There is inconsistent evidence that teriparatide may advance healing of AFFs.

A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery

BACKGROUND AND METHODS In the United States, most patients with primary hyperparathyroidism have few or no symptoms. The need for parathyroidectomy to treat all patients with this disorder has therefore been questioned. We studied the clinical course and development of complications for periods of up to 10 years in 121 patients with primary hyperparathyroidism, 101 (83 percent) of whom were asymptomatic. There were 30 men and 91 women (age range, 20 to 79 years). During the study, 61 patients (50 percent) underwent parathyroidectomy, and 60 patients were followed without surgery. RESULTS Parathyroidectomy in patients with or without symptoms led to normalization of serum calcium concentrations and a mean (+/-SE) increase in lumbar-spine bone mineral density of 8+/-2 percent after 1 year (P=0.005) and 12+/-3 percent after 10 years (P=0.03). Bone mineral density of the femoral neck increased 6+/-1 percent after 1 year (P=0.002) and 14+/-4 percent after 10 years (P=0.002). Bone mineral density of the radius did not change significantly. The 52 asymptomatic patients who did not undergo surgery had no change in serum calcium concentration, urinary calcium excretion, or bone mineral density. However, 14 of these 52 patients (27 percent) had progression of disease, defined as the development of at least one new indication for parathyroidectomy. All 20 patients with symptoms had kidney stones. None of the 12 who underwent parathyroidectomy had recurrent kidney stones, whereas 6 of the 8 patients who did not undergo surgery did have a recurrence. CONCLUSIONS In patients with primary hyperparathyroidism, parathyroidectomy results in the normalization of biochemical values and increased bone mineral density. Most asymptomatic patients who did not undergo surgery did not have progression of disease, but approximately one quarter of them did have some progression.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Report of a Task Force of the American Society for Bone and Mineral Research Running Title: Atypical Femoral Fractures Task Force Report

Reports linking long‐term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross‐linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long‐term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management.

Effects of Daily Treatment with Parathyroid Hormone on Bone Microarchitecture and Turnover in Patients with Osteoporosis: A Paired Biopsy Study*

We examined paired iliac crest bone biopsy specimens from patients with osteoporosis before and after treatment with daily injections of 400 U of recombinant, human parathyroid hormone 1–34 [PTH(1–34)]. Two groups of patients were studied. The first group was comprised of 8 men with an average age 49 years. They were treated with PTH for 18 months. The second group was comprised of 8 postmenopausal women with an average age 54 years. They were treated with PTH for 36 months. The women had been and were maintained on hormone replacement therapy for the duration of PTH treatment. Patients were supplemented to obtain an average daily intake of 1500 mg of elemental calcium and 100 IU of vitamin D. The biopsy specimens were subjected to routine histomorphometric analysis and microcomputed tomography (CT). Cancellous bone area was maintained in both groups. Cortical width was maintained in men and significantly increased in women. There was no increase in cortical porosity. There was a significant increase in the width of bone packets on the inner aspect of the cortex in both men and women. This was accompanied by a significant decrease in eroded perimeter on this surface in both groups. Micro‐CT confirmed the foregoing changes and, in addition, revealed an increase in connectivity density, a three dimensional (3D) measure of trabecular connectivity in the majority of patients. These findings indicate that daily PTH treatment exerts anabolic action on cortical bone in patients with osteoporosis and also can improve cancellous bone microarchitecture. The results provide a structural basis for the recent demonstration that PTH treatment reduces the incidence of osteoporosis‐related fractures.

The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years.

CONTEXT Primary hyperparathyroidism (PHPT) often presents without classical symptoms such as overt skeletal disease or nephrolithiasis. We previously reported that calciotropic indices and bone mineral density (BMD) are stable in untreated patients for up to a decade, whereas after parathyroidectomy, normalization of biochemistries and increases in BMD ensue. OBJECTIVE The objective of the study was to provide additional insights in patients with and without surgery for up to 15 yr. DESIGN The study had an observational design. SETTING The setting was a referral center. PATIENTS Patients included 116 patients (25 men, 91 women); 99 (85%) were asymptomatic. INTERVENTION Fifty-nine patients (51%) underwent parathyroidectomy and 57 patients were followed up without surgery. MAIN OUTCOME MEASURE BMD was measured. RESULTS Lumbar spine BMD remained stable for 15 yr. However, BMD started to fall at cortical sites even before 10 yr, ultimately decreasing by 10 +/- 3% (mean +/- sem; P < 0.05) at the femoral neck, and 35 +/- 5%; P < 0.05 at the distal radius, in the few patients observed for 15 yr. Thirty-seven percent of asymptomatic patients showed disease progression (one or more new guidelines for surgery) at any time point over the 15 yr. Meeting surgical criteria at baseline did not predict who would have progressive disease. BMD increases in patients who underwent surgery were sustained for the entire 15 yr. CONCLUSIONS Parathyroidectomy led to normalization of biochemical indices and sustained increases in BMD. Without surgery, PHPT progressed in one third of individuals over 15 yr; meeting surgical criteria at the outset did not predict this progression. Cortical bone density decreased in the majority of subjects with additional observation time points and long-term follow-up. These results raise questions regarding how long patients with PHPT should be followed up without intervention.

Bone mass, vitamin D deficiency, and hyperparathyroidism in congestive heart failure.

PURPOSE In contrast to renal and hepatic failure, congestive heart failure (CHF) has not been associated with a defined metabolic bone disorder. However, low bone mass has been reported in patients with CHF who receive a cardiac transplant. Both the pathophysiology and therapy of CHF may influence bone and mineral homeostasis and evidence that calciotropic hormones may affect cardiovascular function is accumulating. Therefore, we evaluated patients with severe CHF to determine the prevalence of osteoporosis and to characterize relationships between mineral homeostasis, bone turnover, bone mass, and severity of CHF. PATIENTS AND METHODS One hundred one patients (79 men and 22 women, aged 25 to 70 years) with severe CHF (New York Heart Association functional class III or IV) referred for consideration for cardiac transplantation were evaluated with measurements of serum 25-hydroxyvitamin D (25-OHD), 1,25 dihydroxyvitamin D [1,25(OH)2D], intact parathyroid hormone (PTH), markers of bone turnover (serum osteocalcin, urinary hydroxyproline, and pyridinium crosslinks); bone mineral density (BMD) by dual energy x-ray absorptiometry was measured in 91 patients. Left ventricular ejection fraction (LVEF) and resting cardiac output (CO) were determined in 88 and maximal treadmill exercise testing and peak oxygen consumption were performed in 45 patients. RESULTS Osteoporosis (T score < or = -2.5) was present in 7% at the lumbar spine, 6% at the total hip, and 19% at the femoral neck. Osteopenia (T scores between -1.0 and -2.5) was present in 43% at the lumbar spine, 47% at the total hip, and 42% at the femoral neck. Women were more severely affected (P = 0.007). Frankly low serum 25-OHD (< or = 9 pg/mL) and 1,25(OH)2D (< or = 15 pg/mL) levels were found in 17% and 26% of the patients, respectively, and elevated serum PTH (> or = 65 pg/mL) in 30%. Both low serum 1,25(OH)2D and increased serum PTH were associated with prerenal azotemia. Low serum vitamin D metabolites were associated with biochemical evidence of increased bone turnover, but BMD did not differ by vitamin D or PTH status. Patients with more severe CHF had significantly lower vitamin D metabolites and higher bone turnover, whereas elevated PTH was associated with better LVEF (21 +/- 1 versus 18 +/- 1%; P = 0.05) and correlated positively with resting CO (R = 0.220; P = 0.04). CONCLUSIONS Osteopenia or osteoporosis were observed in approximately half of these patients with severe CHF. Abnormal calciotropic hormone concentrations, also common, were associated with evidence of increased bone resorption but were not related to BMD in this cross-sectional study. Abnormal concentrations of calciotropic hormones were related to the severity of cardiovascular compromise. Because both low BMD and low serum concentrations of 25-OHD in patients with CHF are associated with higher rates of bone loss and fracture after cardiac transplantation, patients should be evaluated for and receive appropriate therapy for these disorders.

Bone Disease in HIV Infection: A Practical Review and Recommendations for HIV Care Providers

Low bone mineral density (BMD) is prevalent in human immunodeficiency virus (HIV)-infected subjects. Initiation of antiretroviral therapy is associated with a 2%-6% decrease in BMD over the first 2 years, a decrease that is similar in magnitude to that sustained during the first 2 years of menopause. Recent studies have also described increased fracture rates in the HIV-infected population. The causes of low BMD in individuals with HIV infection appear to be multifactorial and likely represent a complex interaction between HIV infection, traditional osteoporosis risk factors, and antiretroviral-related factors. In this review, we make the point that HIV infection should be considered as a risk factor for bone disease. We recommend screening patients with fragility fractures, all HIV-infected post-menopausal women, and all HIV-infected men ⩾50 years of age. We also discuss the importance of considering secondary causes of osteoporosis. Finally, we discuss treatment of the more severe cases of bone disease, while outlining the caveats and gaps in our knowledge.

Osteoporosis after organ transplantation

Within the past 2 decades, organ transplantation has become established as effective therapy for endstage renal, hepatic, cardiac, and pulmonary disease. Regimens to prevent rejection after transplantation commonly include high-dose glucocorticoids and calcineurin-calmodulin phosphatase inhibitors (the cyclosporines and tacrolimus), which are detrimental to bone and mineral homeostasis, and are associated with rapid bone loss that is often superimposed upon an already compromised skeleton. The incidence of fracture ranges from 8% to 65% during the first year after transplantation. In general, fracture rates are lowest in renal transplant recipients and highest in patients who receive a liver transplant for primary biliary cirrhosis. Rates of bone loss and fracture are greatest during the first 6 to 12 months after transplantation. Postmenopausal women and hypogonadal men appear to be at increased risk. Although no pretransplant densitometric or biochemical parameter has yet been identified that adequately predicts fracture risk in the individual patient, low pretransplant bone mineral density does tend to increase the risk of fracture, particularly in women. However, patients may sustain fractures despite normal pretransplant bone mineral density. Although the pathogenesis of the rapid bone loss is multifactorial, prospective biochemical data suggest that uncoupling of bone formation from resorption may be in part responsible, at least during the first 3 to 6 months. Prevention of transplantation osteoporosis should begin well before transplantation. Patients awaiting transplantation should be evaluated with spine radiographs, bone densitometry, thyroid function tests, serum calcium, vitamin D, parathyroid hormone, and testosterone (in men). Therapy for osteoporosis, low bone mass, and potentially reversible biochemical causes of bone loss should be instituted during the waiting period before transplantation. In patients with normal pretransplant bone density, therapy to prevent early posttransplant bone loss should be instituted immediately following transplantation. Most pharmacologic agents available for therapy of osteoporosis have not been subject to prospective controlled studies in organ transplant recipients. However, antiresorptive drugs, such as biphosphonates, appear to hold therapeutic promise.

Relationship between Moderate to Severe Kidney Disease and Hip Fracture in the United States

People with ESRD are at a high risk for hip fracture. However, the effect of moderate to severe chronic kidney disease (CKD) on hip fracture risk has not been well studied. As part of the Third National Health and Nutrition Examination Survey, information on both kidney function and history of hip fracture was obtained. This survey is a complex, multistage, probability sample of the US noninstitutionalized civilian population and was conducted between 1988 and 1994. A history of hip fracture was identified from the response to a questionnaire that was administered to all participants. There were 159 cases of hip fracture. There was a significantly increased likelihood of reporting a hip fracture in participants with estimated GFR <60 ml/min (odds ratio [OR] 2.12; 95% confidence interval [CI] 1.18 to 3.80). In younger participants (aged 50 to 74 yr), the prevalence of CKD was approximately three-fold higher in those with a history of hip fracture versus in those without a history of hip fracture (19.0 versus 6.2%, respectively; P = 0.04). In multivariate logistic regression analysis, only the presence of CKD (OR 2.32; 95% CI 1.13 to 4.74), a reported history of osteoporosis (OR 2.52; 95% CI 1.08 to 5.91), and low physical activity levels (OR 2.10; 95% CI 1.03 to 4.27) were associated with a history of hip fracture. There is a significant association between hip fracture and moderate to severe degrees of CKD, particularly in younger individuals, that is independent of traditional risk factors for hip fracture.