Deborah E. Sellmeyer

Microarchitectural deterioration of cortical and trabecular bone: Differing effects of denosumab and alendronate

The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double‐blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high‐resolution peripheral quantitative computed tomography (HR‐pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C‐telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (−2.1% to −0.8%) at the distal radius after 12 months. Alendronate prevented the decline (−0.6% to 2.4%, p = .051 to <.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p ≤ .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab.

Pentosidine and increased fracture risk in older adults with type 2 diabetes

CONTEXT Type 2 diabetes is associated with higher fracture risk at a given bone mineral density. Advanced glycation endproducts (AGEs) accumulate in bone collagen with age and diabetes and may weaken bone. OBJECTIVE The aim was to determine whether urine pentosidine, an AGE, was associated with fractures in older adults with and without diabetes. DESIGN We performed an observational cohort study. SETTING We used data from the Health, Aging and Body Composition prospective study of white and black, well-functioning men and women ages 70-79 yr. PARTICIPANTS Participants with (n = 501) and without (n = 427) diabetes were matched on gender, race, and study site. PREDICTOR Urine pentosidine was assayed from frozen stored baseline specimens. MAIN OUTCOME MEASURES Incident clinical fractures and baseline vertebral fractures were measured. RESULTS Despite higher bone mineral density, clinical fracture incidence (14.8 vs. 12.6%) and vertebral fracture prevalence (2.3 vs. 2.9%) were not lower in those with diabetes (P > 0.05). In multivariable models, pentosidine was associated with increased clinical fracture incidence in those with diabetes [relative hazard, 1.42; 95% confidence interval (CI), 1.10, 1.83, for 1 sd increase in log pentosidine] but not in those without diabetes (relative hazard, 1.08; 95% CI, 0.79, 1.49; P value for interaction = 0.030). In those with diabetes, pentosidine was associated with increased vertebral fracture prevalence (adjusted odds ratio, 5.93; 95% CI, 2.08, 16.94, for 1 sd increase in log pentosidine) but not in those without diabetes (adjusted odds ratio, 0.74; 95% CI, 0.30, 1.83; P value for interaction = 0.005). CONCLUSIONS Higher pentosidine levels are a risk factor for fracture in older adults with diabetes and may account in part for reduced bone strength in type 2 diabetes.

Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research

Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk-benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score, between -2 and -2.5 in FLEX and below -2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered. The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women not at high fracture risk after 3 to 5 years of BP treatment, a drug holiday of 2 to 3 years can be considered. The suggested approach for long-term BP use is based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women, and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future trials will provide data for formulating definitive recommendations.

Diabetes and bone loss at the hip in older black and white adults.

Type 2 diabetes may be associated with elevated fracture risk, but the impact on bone loss is unknown. Analysis of 4‐year change in hip BMD data from a cohort of white and black well‐functioning men and women 70‐79 years of age found that white women with diabetes had more rapid bone loss at the femoral neck than those with normal glucose metabolism.

Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women

Intravenous bisphosphonates reduce fracture risk but have been associated in rare cases with deteriorating renal-function in cancer patients. The renal effects of zoledronic acid were assessed in osteoporotic postmenopausal women from 27 countries who received three annual infusions of zoledronic acid or a placebo in a randomized, double-blind trial. Serum creatinine, estimated creatinine clearance and urinary protein were measured before and after at least one infusion in a predefined renal safety cohort of 5035 equally divided patients. This group was compared to 7714 patients whose parameters were measured annually. Significantly more transient pre- to post-infusion increases in serum creatinine occurred in zoledronic acid than placebo-treated patients with significant elevations, relative to pre-infusion, only in the second year. All 31 zoledronic acid and 8 of 10 patients on placebo recovered their pre-infusion serum creatinine value within 12 months. No differences in mean changes in serum creatinine, estimated creatinine clearance or adverse renal events were found. We found that transient changes in renal function can occur following an annual zoledronic acid infusion but, in the long term, renal function was not different from control patients.

Change in undercarboxylated osteocalcin is associated with changes in body weight, fat mass, and adiponectin: parathyroid hormone (1-84) or alendronate therapy in postmenopausal women with osteoporosis (the PaTH study).

CONTEXT The undercarboxylated form of the osteoblast-secreted protein osteocalcin has favorable effects on fat and glucose metabolism in mice. In human subjects, cross-sectional studies suggest a relevant association. OBJECTIVE We investigated whether changes in undercarboxylated osteocalcin (ucOC) during osteoporosis treatment are associated with changes in metabolic parameters. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS We measured ucOC in sera from a subset of osteoporotic postmenopausal women who were treated with PTH(1-84) or alendronate (n = 64 and n = 33, respectively) during the Parathyroid Hormone and Alendronate study. MAIN OUTCOME MEASURES We measured serum adiponectin, leptin, and insulin and analyzed existing data on body weight, fat mass, and serum glucose concentration. Three-month changes in ucOC levels were evaluated as predictors of 12-month changes in indices of fat and glucose metabolism. RESULTS ucOC levels increased with PTH(1-84) and decreased with alendronate administration (P ≤ 0.01 for both treatment groups). Three-month change in ucOC was inversely associated with 12-month changes in body weight (standardized β = -0.25, P = 0.04) and fat mass (β = -0.23, P = 0.06), after adjustment for the treatment group. Three-month change in ucOC was positively associated with a 12-month change in adiponectin (β = 0.30, P = 0.01), independent of change in fat mass. There were no interactions between treatment and change in ucOC on changes in weight, fat mass, or adiponectin. CONCLUSIONS PTH(1-84) increases and alendronate decreases ucOC levels. Changes in ucOC induced by PTH(1-84) and alendronate are associated with changes in metabolic indices. These associations are consistent with observations from animal models and support a role for ucOC in the skeletal regulation of energy metabolism in humans.

Age-Related Hyperkyphosis: Its Causes, Consequences, and Management

SYNOPSIS Age-related hyperkyphosis is an exaggerated anterior curvature in the thoracic spine that occurs commonly with advanced age. This condition is associated with low bone mass, vertebral compression fractures, and degenerative disc disease, and contributes to difficulty performing activities of daily living and decline in physical performance. While there are effective treatments, currently there are no public health approaches to prevent hyperkyphosis among older adults. Our objective is to review the prevalence and natural history of hyperkyphosis, associated health implications, measurement tools, and treatments to prevent this debilitating condition. LEVEL OF EVIDENCE Diagnosis/prognosis/therapy, level 5.J Orthop Sports Phys Ther 2010;40(6):352-360, Epub 15 April 2010. doi:10.2519/jospt.2010.3099.

Intensive Glycemic Control Is Not Associated With Fractures or Falls in the ACCORD Randomized Trial

OBJECTIVE Older adults with type 2 diabetes are at high risk of fractures and falls, but the effect of glycemic control on these outcomes is unknown. To determine the effect of intensive versus standard glycemic control, we assessed fractures and falls as outcomes in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) randomized trial. RESEARCH DESIGN AND METHODS ACCORD participants were randomized to intensive or standard glycemia strategies, with an achieved median A1C of 6.4 and 7.5%, respectively. In the ACCORD BONE ancillary study, fractures were assessed at 54 of the 77 ACCORD clinical sites that included 7,287 of the 10,251 ACCORD participants. At annual visits, 6,782 participants were asked about falls in the previous year. RESULTS During an average follow-up of 3.8 (SD 1.3) years, 198 of 3,655 participants in the intensive glycemia and 189 of 3,632 participants in the standard glycemia group experienced at least one nonspine fracture. The average rate of first nonspine fracture was 13.9 and 13.3 per 1,000 person-years in the intensive and standard groups, respectively (hazard ratio 1.04 [95% CI 0.86–1.27]). During an average follow-up of 2.0 years, 1,122 of 3,364 intensive- and 1,133 of 3,418 standard-therapy participants reported at least one fall. The average rate of falls was 60.8 and 55.3 per 100 person-years in the intensive and standard glycemia groups, respectively (1.10 [0.84–1.43]). CONCLUSIONS Compared with standard glycemia, intensive glycemia did not increase or decrease fracture or fall risk in ACCORD.

National Institutes of Health Consensus Development Conference: Lactose Intolerance and Health

National Institutes of Health (NIH) consensus and stateof-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality; 2) presentations by investigators working in areas relevant to the conference questions during a 2-day public session; 3) questions and statements from conference attendees during open discussion periods that are part of the public session; and 4) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the U.S. government. The following statement is an abridged version of the panel’s report, which is available in full at http: //consensus.nih.gov/2010/lactosestatement.htm. Lactose intolerance is the syndrome of diarrhea, abdominal pain, flatulence, or bloating occurring after lactose ingestion. These symptoms, which are produced by malabsorption of lactose, a sugar found in milk and other dairy products, often cause afflicted individuals to avoid dairy products in their diets. Lactose malabsorption is caused by a decreased ability to digest lactose that is due to a deficiency in the levels of the enzyme lactase. Lactase breaks lactose down into 2 simpler sugars, glucose and galactose, which are readily absorbed into the bloodstream. This enzyme is produced by expression of the lactase‐phlorizin hydrolase gene in the cells lining the small intestine. All infants produce lactase and successfully digest lactose provided by human milk or by infant formulas. However, sometime after weaning, a genetically programmed decrease in lactase (lactase nonpersistence) occurs in most children worldwide. The symptoms of lactose intolerance result from bacterial fermentation of undigested lactose in the colon. Lactose malabsorption can be diagnosed by having individuals ingest a standard dose of lactose after fasting and measuring breath hydrogen; elevated breath hydrogen levels are caused by bacterial fermentation of undigested lactose in the colon. Other diagnostic tools include measuring lactase activity in an intestinal biopsy sample or genetic testing for the common polymorphism that is linked to lactase nonpersistence. The demonstration of lactose malabsorption does not necessarily indicate that an individual will have symptoms. Many variables determine whether a person who malabsorbs lactose develops symptoms, including the dose of lactose ingested, the residual intestinal lactase activity, the ingestion of food along with lactose, the ability of the colonic flora to ferment lactose, and individual sensitivity to the products of lactose fermentation.

Fat infiltration of muscle, diabetes, and clinical fracture risk in older adults

CONTEXT Older adults with type 2 diabetes are at higher risk for fracture compared with nondiabetic adults after adjustment for their higher bone mineral density. Infiltration of muscle by fat predicts increased risk of hip fracture. OBJECTIVE We investigated whether fat infiltration of muscle, which is greater in diabetic adults, is associated with all clinical fracture and whether it accounts for the increased fracture risk in those with diabetes. DESIGN, SETTING, AND PARTICIPANTS Data were analyzed from the Health, Aging, and Body Composition Study, a cohort of community-dwelling adults aged 70-79 yr. Glucose metabolism status and x-ray attenuation of thigh muscle were determined at baseline for 2762 participants. MAIN OUTCOME MEASURES During a mean 8.2 ± 2.3 yr follow-up, 331 participants reported at least one clinical fracture. RESULTS Fat infiltration of muscle was higher in those with diabetes or impaired glucose metabolism than in those with normal glucose metabolism (P < 0.001). Fat infiltration of muscle was independently associated with a 19% increased risk of incident clinical fracture (multivariate hazard ratio = 1.19; 95% confidence interval = 1.04-1.36); this association did not differ across glucose metabolism groups (P for interaction = 0.65). As previously reported, diabetes was associated with a greater fracture risk compared with normal glucose metabolism (hazard ratio = 1.42; 95% confidence interval = 1.07-1.89) after adjustment for bone mineral density, but further adjustment for fat infiltration of muscle did not attenuate this association. CONCLUSIONS Fat infiltration of muscle predicts clinical fracture in older adults. Although fat infiltration of muscle is higher among those with diabetes, it does not account for their increased fracture risk.