Craig D. Rubin

Emerging concepts in osteoporosis and bone strength

ABSTRACT Objective: Osteoporosis is a systemic skeletal disorder characterized by compromised bone strength and increased fracture risk. The factors that contribute to bone strength include bone mineral density (BMD) and bone quality, which encompasses factors such as bone turnover, microarchitecture, mineralization, and geometry. The objective of this paper was to review the factors that contribute to bone strength and osteoporosis. Research design: A MEDLINE search of English language journals between 1 January 1995 and 1 March 2005 was conducted using the term ‘osteoporosis’ combined with ‘bone strength’ or ‘bone quality’. Reference lists of pivotal studies and reviews were also examined. Studies were otherwise not excluded on the basis of quality or size, the aim being to present an overview of research conducted to date on osteoporosis and bone strength. Results: While there is a relationship between BMD and fracture risk, evidence suggests that BMD measurements reflect only 1 component of bone strength. For example, small changes in BMD produced by osteoporosis treatments do not fully explain the reductions in fracture risk observed after initiation of therapy, and substantial fracture risk reduction is observed before peak increases in BMD are achieved. In addition to their effects on BMD, anti-resorptive therapies for osteoporosis (i.e., bisphosphonates, selective estrogen receptor modulators, calcitonin, and estrogen) produce positive effects on bone turnover, microarchitecture, and/or mineralization, all of which can contribute to the reductions in fracture risk observed with these agents. Anabolic agents such as teriparatide also appear to have beneficial effects on bone strength independent of bone mass. New, non-invasive, high-resolution imaging methods, such as magnetic resonance imaging and computed tomography, may offer a comprehensive assessment of bone quality in the future. Conclusions: The development of clinical tools that assess bone quality independent of BMD will be essential to advance our assessment of fracture risk and response to osteoporosis treatment.

A Randomized, Controlled Trial of Outpatient Geriatric Evaluation and Management in a Large Public Hospital

Objective: To study the effect of outpatient geriatric evaluation and management on physical function, mental status, and subjective well‐being.

The Effect of Geriatric Evaluation and Management on Medicare Reimbursement in a Large Public Hospital: A Randomized Clinical Trial

Objective: To study the effect of a geriatric evaluation and management program on health care charges and Medicare reimbursement.

Development of Geriatrics-Oriented Faculty in General Internal Medicine

The need for all medical students and primary care housestaff to acquire skills in the care of the elderly has been recognized for decades (1, 2). More recently, studies have shown that fellows training in general internal medicine and internal medicine subspecialties need to develop these skills as well (3). It was hoped that faculty with geriatrics training or expertise could meet the educational needs of trainees; however, we continue to have insufficient numbers of academic geriatricians, and this shortage will worsen in the future (46). Clinicianeducators in general internal medicine do much of the teaching of trainees in both ambulatory and inpatient settings, where many of the patients are elderly. Thus, academic general internists have the opportunity to help impart the basic knowledge and skills necessary to care for older adults (7). To incorporate geriatrics into their already busy teaching agendas, general internists must have the necessary motivation, knowledge, and skills. We describe what is being done to develop geriatrics-oriented general internal medicine faculty. We identify current practices, best practices, goals and targets, and barriers to achieving those goals and targets. We then offer potential solutions for overcoming barriers to faculty development in geriatrics among academic general internists. Methods Literature Review We searched the literature using several databases: MEDLINE (1966 to February 2001), ERIC (Educational Resources Information Center) (1966 to February 2001), AgeLine (1978 to February 2001), Best Evidence (1991 to February 2001), Current Contents (1995 to February 2001), the Cochrane Database of Systematic Reviews, and Pre-MEDLINE. Abstracts from national meetings of the American Geriatrics Society and the Society of General Internal Medicine were reviewed for the years 1999 to 2001. Program reports on geriatrics-oriented faculty-development activities were requested from the John A. Hartford Foundation, Inc., and the Health Resources and Services Administration. We also asked leaders in geriatric medicine about their knowledge of programs related to geriatrics-oriented faculty development in general internal medicine. We reviewed titles and available abstracts for a match to at least 1 of 6 areas: current practices, best practices, goals and targets for optimal development of geriatrics-oriented general internal medicine faculty, barriers to achieving those goals and targets, solutions to identified barriers, and institutions that have programs and have published in the area of geriatrics-oriented faculty development. Two authors reviewed articles for the following inclusion criteria: 1) inclusion of general internal medicine faculty, 2) description of the educational interventions, 3) evaluation of the outcomes, and 4) description of the outcomes. The literature review identified a total of 504 references. We reviewed all titles and available abstracts (64%) and read 138 articles in their entirety. Four published articles and 3 program project reports (814) (Appendix Table) met the inclusion criteria. Focus Group and Structured Interviews As a convenience sample, 40 division heads of general internal medicine units at 38 medical schools in the southern United States were asked to participate in an 80-minute focus-group session on training general internists in geriatrics. We used a random-numbers table to select 34 other medical schools for interviewing. We sent letters to the general internal medicine chiefs at those schools, requesting their participation in a structured 15-minute telephone interview. We also sent letters to the directors and the heads of general internal medicine of 21 Hartford Centers of Excellence. Results Literature Review The faculty-development projects described in the literature or project reports were all funded by 1 of 2 sources: the Health Resources and Services Administration, as part of its Geriatrics Education Centers in the 1980s, or the John A. Hartford Foundation, Inc., in the 1990s. All faculty-development activities included faculty from more than 1 discipline. The interventions ranged from 9 evening sessions held over 3 years (9) to 1 year of on-site training (10). They all included educational modules related to geriatrics content and training in educational methods. A few included experiential training at geriatric clinical sites or teaching, or both (Appendix Table) (10, 11; Silliman R. John A. Hartford Foundation Progress Report. Boston University Center of Excellence in Geriatrics: 1/1/98 to 12/31/00, 2001, Personal communication; Stratos G. Final Report: Stanford Education Resource and Dissemination Center for the John A. Hartford Geriatrics in Primary Care Residency Training Initiatives, 2001, Personal communication). All of the faculty-development projects measured outcomes by using surveys and evaluations of educational offerings at or after the conclusion of the projects. They also measured either 1) the intent of participating faculty to change geriatrics practice or teaching or 2) self-reported change in the activities of participating faculty at some point after the training. Only 1 project (Stratos G. Personal communication) measured and reported change in knowledge, skills, and attitude by learners. None of the projects measured change in behavior by learners that might have resulted from the educational intervention. Focus Group and Structured Interviews Eleven of the 40 division heads, representing 10 schools, participated in the focus-group session. We completed interviews with 13 Hartford Center directors (62%), 21 general internal medicine unit chiefs at medical schools that are not Centers of Excellence (62%), and 9 general internal medicine unit chiefs at schools with a Hartford Center (43%). Between the focus group and the individual interviews, 49 medical schools were represented. According to general internal medicine unit chiefs, geriatrics was taught exclusively by geriatrics faculty at 24% of schools that are not Centers of Excellence and 67% of schools with Hartford Centers. It was taught by both general internal medicine and geriatrics faculty at 38% of schools that are not Centers of Excellence and 33% of schools with Hartford Centers. It was taught exclusively by general internal medicine faculty at 33% of schools that are not Centers of Excellence and none of the schools with Hartford Centers. At 1 school, internists did not teach geriatrics. At 3 of the 5 schools with Hartford Centers where both the Center director and the general internal medicine unit chief were interviewed, the director and the chief disagreed about who taught geriatrics. When asked whether geriatrics should be taught by general internal medicine faculty, general internal medicine unit chiefs said yes at 86% of schools that are not Centers of Excellence and at 56% of schools with Hartford Centers. When Center directors were asked the same question, 85% said yes. General internal medicine unit chiefs were asked whether their faculty perceived that they should teach geriatrics. At schools that are not Centers of Excellence, 57% said yes and 52% said that their faculty currently had the knowledge and skills to teach geriatrics (81% concordance). At schools with Hartford Centers, 22% said yes and 33% said that their faculty currently had the knowledge and skills to teach geriatrics (87.5% concordance). When Hartford Center directors were asked whether their general internal medicine faculty had the knowledge and skills to teach geriatrics, 46% said yes. Activities to increase clinical or teaching skills in geriatrics for general internal medicine faculty were reported by 5 (24%) of the general internal medicine unit chiefs at schools that are not Centers of Excellence, 5 (56%) of the general internal medicine unit chiefs at schools with Hartford Centers, and 4 (31%) of the Hartford Center directors. Some Center directors noted that although geriatrics-oriented faculty-development activities were offered to general internal medicine faculty, few or no faculty participated. The rest of the reported activities were done as part of ongoing general internal medicine unit activities, such as journal clubs, grand rounds, and conferences. Outcomes have not been measured or published for most of these activities, many of which were not sustained over time. At Hartford Centers, we identified 2 additional faculty-development programs for which outcomes have not been published. At 1 site, faculty members received a small stipend, participated in didactic work, and were paired with geriatricians who helped them develop a scholarly project. The intervention does not seem to have had a measurable effect on the teaching of geriatrics by general internal medicine faculty at this institution. Another program offered support to assist general internal medicine faculty with the development of core geriatrics content areas for teaching. As a result, general internal medicine faculty and geriatrics faculty provide didactic lectures during resident and student geriatrics rotations. The general internal medicine chiefs were asked in an open-ended manner to identify existing barriers that hinder their faculty from teaching geriatrics and participating in geriatrics-oriented faculty development. Nineteen (70%) specified lack of time, both for teaching and for participation in faculty development. Ten (37%) suggested that their faculty did not perceive a need to teach geriatrics or were not motivated to teach geriatrics. Some identified a lack of resources as a barrierspecifically, materials for geriatrics-oriented faculty development and clinical resources to enable interdisciplinary teams to teach geriatrics. Although the focus-group participants were a subset of a regional group of general internal medicine unit chiefs, their responses yielded information similar to that offered in the structured interviews. Discussion Our findings suggest a great

Southwestern Internal Medicine Conference: Age-Related Osteoporosis

Osteoporosis is a common disease that results in 1.2 million fractures each year in the United States. The morbidity and mortality as well as the financial impact from this disease is substantial. There has been considerable progress in our understanding of this disorder, but studies commonly include only early postmenopausal individuals. At the same time, it is clear that there are major epidemiologic, physiologic, and clinical differences between early postmenopausal and older individuals. These considerations raise the issue of the appropriateness of generalizing evaluation and treatment recommendations from younger to older patients. This review will focus on the age-related changes in bone physiology as it relates to osteoporosis and consider the available evidence for using commonly used (calcium) or approved (estrogen and calcitonin) agents in the elderly patient.

Treating a Patient with the Werner Syndrome and Osteoporosis Using Recombinant Human Insulin-like Growth Factor

The Werner syndrome is a rare autosomal recessive disorder that in many ways resembles premature aging [1, 2]. At an early age, patients commonly develop cataracts, atherosclerosis, malignancies, and osteoporosis [3]. Because of the frequency of osteoporosis, the Werner syndrome may provide an insight into the pathogenesis and treatment of age-related bone loss. We have previously described the histomorphometric and biochemical indices of bone in a 43-year-old woman with the Werner syndrome and severe osteoporosis [4]. This patient was shown to have a low circulating concentration of insulin-like growth factor 1 (IGF-1). Diminished IGF-1 synthesis may contribute to osteoblastic suppression and bone loss because IGF-1 stimulates bone formation by increasing osteoblastic activity [5, 6]. The impairment with age in the growth hormone-insulin-like growth factor axis and resulting decrease in circulating IGF-1 levels have been implicated in the age-related decrease in lean body mass and bone mass [7]. However, an exact causal relation between reduced serum IGF-1 levels and osteoporosis has not been established [8]. Because examination of bone biopsy specimens showed that our patient had reduced osteoblastic activity in addition to low serum IGF-1 levels, we felt she would be an ideal candidate in whom to assess both the safety of recombinant human IGF-1 (rhIGF-1) and its effect on bone metabolism. We report the results of 6 months of daily subcutaneous doses of rhIGF-1. Case Report Our patients clinical presentation has been previously described and shows the typical history and physical findings of patients with the Werner syndrome [4]. Although menopause occurred when the patient was 31 years old, she began receiving conjugated estrogens and progesterone a few months after her last menstrual period and continued to receive them up to and throughout the study. Initial evaluation at our institution excluded secondary causes of osteoporosis. Skeletal radiographs showed marked radiolucency and compression fractures of almost all thoracic and lumbar vertebrae. Bone mineral densities (measured by QDR-2000; Hologic, Waltham, Massachusetts) of the L2 to L4 vertebrae, femoral neck, and radial shaft were 2.38, 3.93, and 2.0 standard deviations lower than the means for age-matched normal women, respectively. A transcortical iliac crest bone biopsy was done after tetracycline labeling [9]. The histomorphometric data were consistent with a suppressed bone formation rate in light of the normal bone resorption rate [4]. Methods The Institutional Review Board of the University of Texas Southwestern Medical Center reviewed and approved the study protocol, and the patient gave informed consent for participation in the study. The patient underwent four study phases, each lasting 4 days in the inpatient setting of the general clinical research center. The control phase took place before rhIGF-1 treatment was initiated. The patient continued to receive routine medications, including calcium citrate (200 mg of elemental Ca twice a day) and estradiol transdermal system (0.05 mg twice a week). She was kept on a constant metabolic diet consisting of 800 mg of calcium, 800 mg of phosphorus, and 100 mEq of sodium. On days 1 to 3, urine was collected in three consecutive 24-hour pools for urinary calcium, phosphorus, sodium, hydroxyproline, creatinine, and pyridinoline cross-links. We obtained fasting venous blood samples on days 1 through 4 to measure routine chemistries and intact parathyroid hormone, osteocalcin, type I procollagen C-peptide, and IGF-1 levels [10]; on day 1, we obtained a blood sample to measure 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels [11]. We determined intestinal fractional calcium absorption using fecal recovery of orally administered Calcium-47 [12]. Because diurnal variations have been reported with serum procollagen levels [13], we obtained venous blood samples every 4 hours for 24 hours on day 2 to determine diurnal levels of serum type I procollagen C-peptide. We determined bone mineral densities of the L2 to L4 vertebrae and the femoral neck using quantitative digital radiography (Hologic QDR 2000) and the bone density of the distal one third of the radius using a Norland single-photon absorptiometer (Madison, Wisconsin). Standing anterior-posterior and lateral radiographs of the thoracic and lumbar spine were also done. After we completed the baseline evaluation (control phase), the patient was treated with rhIGF-1. (Genentech [South San Francisco, California] provided rhIGF-1 [IND#39397] free of charge but gave no other support.) The drug was administered subcutaneously starting at 30 g/kg of body weight per day. At this dose, serum IGF-1 levels increased from low to normal levels that were age- and sex-matched (Figure 1). At 6 weeks, the dose was increased at increments of 15 g/kg per day to 45 g/kg per day, at 8 weeks to 60 g/kg per day, and at 10 weeks to 75 g/kg per day. Although no side effects were found at the latter dose, the serum IGF-1 level was abnormally high at 1000 ng/mL; the dose was therefore reduced to 60 g/kg per day for weeks 19 to 26. Figure 1. Serum insulin-like growth factor type 1 (IGF-1) and IGF-1-binding protein-3 (IGF-1-BP-3) levels before and during treatment with recombinant human IGF-1. The patient was readmitted to the general clinical research center after 1 month, 3 months, and 6 months of treatment. Evaluations identical to those of the control phase were done. In addition to receiving inpatient evaluations, the patient was seen as an outpatient weekly during the first 6 weeks of therapy and every 2 weeks thereafter to monitor for side effects. Results Symptoms The patient tolerated the administration of rhIGF-1 with no identifiable side effects. Body weight remained stable during treatment with rhIGF-1. We found no evidence of increased intracranial pressure such as papilledema or hypoglycemic symptoms. She reported having less discomfort in her feet and an improved sense of well-being. Serum Insulin-like Growth Factor-1 and Insulin-like Growth Factor-Binding Protein-3 Concentration As described previously, a single daily subcutaneous dose of rhIGF-1 (30 g/kg per day) could increase circulating IGF-1 levels from low to normal (Figure 1). Doses greater than 30 g/kg per day resulted in proportionally higher levels of circulating IGF-1. Random measurements showed that the serum IGF-binding protein-3 level remained normal during therapy. Markers and Measures of Bone Metabolism Serum calcium, phosphorus, and alkaline phosphatase levels did not change from baseline (Table 1). Serum osteocalcin and type I procollagen C-peptide increased at 1 month and remained elevated throughout therapy. Diurnal changes in serum type I procollagen C-peptide showed that values at 3 and 6 months of treatment were greater than those at baseline (data not shown). The mean serum type I procollagen C-peptide concentrations over 24 hours while the patient received rhIGF-1 therapy were statistically significantly higher than the baseline values. Table 1. Serum, Urine, and Bone Mineral Density Values before and during Therapy with Recombinant Human Insulin-like Growth Factor 1* Twenty-four-hour urinary calcium, hydroxyproline, and pyridinoline levels were higher after treatment with rhIGF-1 than before treatment (Table 1). The urinary pyridinoline level was lower at 6 months than at 3 months but remained elevated over the baseline value during all treatment phases. Bone Density and Intestinal Calcium Absorption During 6 months of treatment, the bone mineral density of the L2 to L4 vertebrae increased 3% (Table 1). However, the bone mineral densities of the femoral neck and radial shaft did not change. No new spinal fractures were shown on radiographs done during the study. Intestinal calcium absorption was in the low normal range (normal, 40% to 60%) [14] at baseline and was the same after 6 months of rhIGF-1 treatment. Absorption was approximately 12% higher during the first and third months of treatment. No significant changes were noted in serum values for 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and parathyroid hormone levels. Other Tests Other biochemical measurements before and during therapy with rhIGF-1 are listed in Table 1. Fasting serum glucose, cholesterol, and triglyceride levels did not change. We found no disturbances in serum electrolytes, liver enzymes, or measures of renal function. Discussion The administration of rhIGF-1 increased several biochemical markers of bone turnover. Serum type 1 procollagen C-peptide and osteocalcin levels, both markers of bone formation, increased, although total serum alkaline phosphatase levels did not change. Urinary pyridinoline cross-links and hydroxyproline, both measures of bone resorption, increased with rhIGF-1 therapy compared with baseline values. Moreover, 24-hour urinary calcium levels increased in the absence of increased intestinal calcium absorption or serum 1,25-dihydroxyvitamin D, suggesting that bone was the source of increased urinary calcium. Two reports of 1 week of treatment with rhIGF-1 have described increased bone turnover in normal postmenopausal women and in a man with idiopathic osteoporosis [14, 15]. In our patient being treated with transdermal estrogen, exogenous IGF-1 overcame the antiresorptive action of estrogen. Despite the short duration of treatment, bone mineral density at the lumbar spine increased in excess of the coefficient of variation (2%) of the instrument used. Because bone mass measured at the femoral neck and radial shaft did not change compared with baseline values, the apparent gain in bone mass in the spine was probably not caused by bone redistribution but rather by increased bone formation in excess of resorption. A single daily dose of rhIGF-1 administered subcutaneously at a dosage of 30 to 75 g/kg per day was sufficient to increase the circulating IGF-1 level to normal and greater-th

Characterization of Osteoporosis in a Patient with Werner's Syndrome

erner’s syndrome is a rare autosomal recessive disorder which has many clinical features reW sembling advanced age. Although it would be erroneous to describe this condition as a disorder of premature agng, it could be characterized as a “caricature of aging.”’ Patients with this disease commonly develop cataracts, atherosclerosis, malignancies, and osteoporosis.* Because of the occurrence of these medical illnesses common to the elderly, Werner’s Syndrome has been viewed with interest as possibly providing insight into age-related medical problems. Osteoporosis is one such problem that is common in the elderly and has been reported to be resent in as high as 100% of patients with Werner’s!*’ However, little information is available regarding the characterization of osteoporosis in these patients. Most reports are limited to descriptions of the radiographic appearance of the bones, showing radiolucency and fractures, particularly of the distal e~tremities.~ It is known that either excessive bone resorption or inadequate or reduced bone formation can result in osteoporosis. Although considerable individual variation exists, impaired bone formation is believed to characterize age-related osteoporosis. Elucidation of the pathophysiology of osteoporosis in patients with Werner’s syndrome would be useful in establishing whether the bone disease resembles that of age-related osteoporosis. We recently had the opportunity to intensively evaluate a patient with Werner’s syndrome. The following are the findings of this investigation.

Donepezil effects on hippocampal and prefrontal functional connectivity in Alzheimer's disease: preliminary report.

We used functional connectivity magnetic resonance imaging (fcMRI) to investigate changes in interhemispheric brain connectivity in 11 patients with mild Alzheimers disease (AD) following eight weeks of treatment with the cholinesterase inhibitor donepezil. We examined functional connectivity between four homologous temporal, frontal, and occipital regions. These regions were selected to represent sites of AD neuropathology, sites of donepezil-related brain activation change in prior studies, and sites that are minimally affected by the pathologic changes of AD. Based on previous findings of selective, localized frontal responses to donepezil, we predicted that frontal connectivity would be most strongly impacted by treatment. Of the areas examined, we found that treatment had a significant effect only on functional connectivity between right and left dorsolateral prefrontal cortices. Implications for understanding the impact of donepezil treatment on brain functioning and behavior in patients with AD are discussed. This preliminary report suggests that fcMRI may provide a useful index of treatment outcome in diseases affecting brain connectivity. Future research should investigate these treatment-related changes in larger samples of patients and age-matched controls.

The Primary Care of Alzheimer Disease

Alzheimer disease is the most common cause of progressive irreversible intellectual loss in aging humans. The number of individuals and families affected by this disorder will continue to grow as society ages worldwide. Our understanding of the biology, underlying pathophysiology, and diagnosis of Alzheimer disease has greatly expanded over the past few years and much has been published in these areas. This review focuses on the primary care of this disorder and addresses the “now what” question. Topics examined include limiting excess disability, responding to commonly raised questions of family members, pharmacologic and nonpharmacologic therapeutic options, long-term planning, and caregiver issues.

Evaluation and management of hip fracture risk in the aged

Hip fractures are common and a major national health concern. According to the National Center for Health Statistics,1 in 2004, there were more than 320,000 hospital admissions for hip fractures. The first year death rate after hip fracture is approximately 30%, which is above that of age-matched controls2 and remains increased compared with age-matched controls even after 10 years of follow-up. Although some studies have suggested a recent decline in the incidence and mortality related to hip fractures after adjusting for the increasing age of the U.S. population,3,4 the sheer growth in the segment of our population most vulnerable to hip fracture, those older than 80 years, will continue to grow more rapidly than any other segment of our population during the next 3 decades. By 2040, it has been estimated that there will be well more than 500,000 hip fractures a year in the United States.5 Hip fractures frequently result in a decline in functional status and a need for assistance with activities of daily living. This associated decline in function frequently results in loss of independence and requires up to 20% of patients previously living independently to move to long-term care facilities for at least a year after their fracture.6–8 The direct and indirect costs for the individual, their family and the taxpayer are staggering and will only increase.6 The Centers for Disease Control has estimated that by 2020 the annual direct and indirect cost of injuries related to falls will reach nearly