OSTEOPOROSIS CURRENTLY AFFECTS approximately

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1 X/05/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 90(6): Printed in U.S.A. Copyright 2005 by The Endocrine Society doi: /jc Low Bone Formation in Premenopausal Women with Idiopathic Osteoporosis Marcella A. Donovan, David Dempster, Hua Zhou, Donald J. McMahon, Jessica Fleischer, and Elizabeth Shane Department of Medicine (M.A.D., D.J.M., J.F., E.S.), College of Physicians and Surgeons, Columbia University, New York, New York 10032; and Regional Bone Center (D.D., H.Z.), Helen Hayes Hospital, West Haverstraw, New York OSTEOPOROSIS CURRENTLY AFFECTS approximately 10 million Americans. Although osteoporosis is most frequent among postmenopausal women, premenopausal women and men may also be affected. Most young people with osteoporosis have an identifiable cause, in that they have an underlying disorder or medication exposure that has either impeded peak bone mass acquisition during adolescence or caused excessive bone loss after peak bone mass was attained (1). Others have idiopathic osteoporosis, for which no contributory etiology can be found. Idiopathic osteoporosis has been variably defined in the literature. Some reports include only individuals who have had low trauma or atraumatic (fragility) fractures, whether or not they have low bone mineral density (BMD) measurements (1, 2). Other reports also include individuals with low BMD measurements who do not have fractures (2 4). If defined by the occurrence of fragility fractures, idiopathic osteoporosis is uncommon, with an estimated incidence of 0.4 cases per 100,000 person-years, and appears to occur with almost equal frequency in men and women (1). Most of the reported cases of idiopathic osteoporosis are in Caucasians, and the usual clinical history is one of multiple nontraumatic fractures, involving predominantly cancellous bone, over the years preceding presentation (1 3). A number of studies have attempted to investigate the pathophysiology of idiopathic osteoporosis. In a rigorous, First Published Online March 22, 2005 Abbreviations: BMD, Bone mineral density; BMI, body mass index. JCEM is published monthly by The Endocrine Society ( endo-society.org), the foremost professional society serving the endocrine community. Most young people with osteoporosis have an identifiable cause. Others have an idiopathic form for which no etiology can be found. We have reported that men with idiopathic osteoporosis (IOP) have histomorphometric evidence of decreased bone formation and osteoblast dysfunction. The pathogenesis of IOP in young women remains unclear. Our aim was to characterize the histomorphometry of IOP in healthy premenopausal women. We compared iliac crest bone biopsies from nine women with IOP to 18 healthy, age-, sex-, and race-matched controls. Compared with controls, differences in bone remodeling were identified, particularly in cancellous bone. Although cancellous bone volume did not differ, there was a trend toward lower trabecular number and increased separation in women with IOP. In cancellous bone, there was no increase in osteoid width or perimeter, but IOP patients had lower bone formation parameters, including a 10% reduction in wall width (P 0.01), an 18% reduction in mineral apposition rate (P 0.01), and a 42% reduction in mineralized perimeter (P 0.02). Additionally, the bone formation rate was 52% lower ( vs m/ m 2 d; P 0.01), and a trend toward decreased activation frequency was observed in IOP patients. Conversely, bone resorption was altered in IOP patients, reflected by a longer resorption period ( vs. 38 6d;P 0.02) and increased eroded perimeter ( vs %; P 0.05). Wall width and mineralized perimeter were similarly lower in endocortical bone. Resorption period and eroded perimeter were higher in intracortical bone. Women with IOP have uncoupling of resorption and formation and, like men with IOP, osteoblast dysfunction. (J Clin Endocrinol Metab 90: , 2005) retrospective study, Khosla et al. (1) examined the histomorphometric features of a group of young men and women with idiopathic osteoporosis defined on the basis of fragility fractures. Cancellous bone volume, cortical width, and mean wall thickness were significantly reduced, and eroded surface was increased in osteoporotic subjects compared with normals. Bone turnover, however, as reflected by bone formation rates and activation frequency, was variable, without consistent differences from normal subjects. The decrease in mean wall thickness suggested that impaired osteoblast function might be a feature of idiopathic osteoporosis. Subsequent studies have further elucidated the pathophysiology of idiopathic osteoporosis in men. Men with idiopathic osteoporosis clearly have histomorphometric evidence of decreased bone formation and osteoblast dysfunction (5 7). Moreover, serum IGF-I levels are reduced in men with idiopathic osteoporosis (7, 8) and correlate with and may contribute to the abnormalities in bone remodeling demonstrated by histomorphometry (7). IGF-I levels are normal, however, in premenopausal women with idiopathic osteoporosis (4, 9), suggesting that the etiology of idiopathic osteoporosis in women may differ from men. Few histomorphometric data are available in women with idiopathic osteoporosis. Most studies investigating the histomorphometric findings in women with idiopathic osteoporosis involved pooled data from both sexes (1, 10), have grouped women with idiopathic and known causes of osteoporosis together (11 14), or compared women with idiopathic osteoporosis with controls with other metabolic bone diseases (11, 12). Thus, the pathogenesis of idiopathic osteoporosis in premenopausal women remains unclear. Because of the dearth and conflicting nature of the available data, we 3331

2 3332 J Clin Endocrinol Metab, June 2005, 90(6): Donovan et al. Idiopathic Osteoporosis in Premenopausal Women conducted a retrospective chart review to identify young, otherwise healthy women, who presented to our center with fragility fractures and underwent a transiliac bone biopsy as part of their evaluation. Our aim was to characterize the histomorphometric features of idiopathic osteoporosis in otherwise healthy premenopausal women and compare them with normal controls. Patients and Methods This study was a case-control comparison of histomorphometric data from premenopausal women with unexplained fragility fractures, who underwent percutaneous transiliac crest biopsy, and age-, sex-, and race-matched controls. Patients were evaluated in the Metabolic Bone Diseases Unit at Columbia-Presbyterian Medical Center (CPMC) over a 10-yr period. Bone biopsies were analyzed at the Regional Bone Center, Helen Hayes Hospital. All subjects provided written informed consent, and the studies were approved by the Institutional Review Boards of both CPMC and the Helen Hayes Hospital. Study population Between 1990 and 2001, nine healthy premenopausal women, who presented to our clinic with fragility fractures, underwent tetracyclinelabeled transiliac crest bone biopsy after secondary causes of osteoporosis were excluded by history, physical examination, and biochemical testing. All subjects had undergone an extensive assessment at the Metabolic Bone Diseases Unit of CPMC at the time of presentation. Idiopathic osteoporosis was defined in each case by the presence of one or more fragility fractures and exclusion of known secondary causes of osteoporosis by the clinician involved in the patient s care. All patients had regular menses, and none had a past history of amenorrhea. No patient had a history or biochemical evidence of Cushing s syndrome, primary or secondary hyperparathyroidism, vitamin D deficiency, malabsorption, celiac disease, hypercalciuria, renal dysfunction, thyrotoxicosis, vitamin A toxicity, hyperphosphaturia, malignancy, alcoholism, osteogenesis imperfecta, Marfan s syndrome, or medication-induced bone disease. BMD by dual-energy x-ray absorptiometry was performed as a part of the evaluation, but low BMD, as defined by T-score or Z-score, was not used as a criterion for diagnosis, because each patient had at least one fragility fracture. A fragility fracture was defined as a minimal trauma (fall from standing height or less) or nontraumatic fracture, occurring after age 18. Using World Health Organization criteria developed for Caucasian postmenopausal women, eight of nine study subjects had osteopenia (T-score between 1.0 and 2.49) or osteoporosis (T-score 2.5) at the lumbar spine, total hip, femoral neck, or forearm plus a fragility fracture. One patient had established osteoporosis on the basis of multiple low-trauma hip fractures, yet had normal T-scores at all sites. For this analysis, relevant clinical data were extracted from the medical record. Subjects were compared with 18 age-, race-, and sex-matched normal controls. Controls were from our previous study comparing histomorphometric parameters in black and white healthy premenopausal women (15). Control subjects were free of conditions or medications known to affect bone metabolism and had no clinical evidence of any form of bone disease. They were normal with respect to blood counts, routine biochemistries, urinalysis, thyroid function, estradiol, and FSH, PTH, vitamin D, and urinary calcium levels. The bone biopsies from both subjects and controls were remeasured and reanalyzed for the purposes of this case-control study in the same laboratory by the same individual and using the same procedures. Biopsy Approximately 1 month before the biopsy, women were prelabeled with tetracycline taken orally in two time-spaced cyclical doses of tetracycline hydrochloride (Sumycin 250 mg four times daily) and demethylchlortetracycline (Declomycin 150 mg four times daily) following a 3 d on, 14 d off, 3 d on, 5- to 7-d free schedule. Transiliac bone biopsy was performed according to standard technique (16). Bone histomorphometry Methods of tissue processing, sectioning, and staining followed established procedures (17, 18). Histomorphometry was performed by using a digitizing image-analysis system, consisting of microscopy with normal and UV light, a high-resolution three-chips color video camera, a tablet, a computer and its display, and a morphometric program (OsteoMeasure; OsetoMetrics, Inc., Atlanta, GA). All variables were expressed and calculated according to the recommendations of the American Society for Bone and Mineral Research nomenclature committee (19). Bone structure. Conventional indices of bone structure were evaluated on Goldner-stained, 7- m-thick sections. Before measurements, the cancellous space and cortices were precisely demarcated by well-established criteria (20). The cancellous bone volume, trabecular number, trabecular width, and trabecular separation were derived from the measurement of total tissue area, cancellous bone area, and perimeter. Cortical width was measured after defining the periosteal and endocortical surfaces. The enlarged cortical Haversian canal with active or quiescent surface was defined as cortical porosity, and its number was measured by number counting. The measurements of bone structure parameters were performed at 20 magnification. Bone remodeling. Osteoid parameters (osteoid perimeter and osteoid width) were measured on 7- m-thick sections with the solochrome cyanine R stain, eroded perimeter was measured on the sections with Goldner s trichrome stain and tetracycline label parameters (mineralizing perimeter, mineral apposition rate, and bone formation rate) were measured or derived from the measurement on the 20- m-thick unstained sections. Perimeter indices were expressed as percentages of bone perimeter on cancellous, endocortical, and intracortical or enlarged cortical Haversian canal surfaces separately. Mineralized perimeter was calculated by the extent of all double labels plus half the extent of single labels. The mineral apposition rate was calculated from the measurement of interlabel distance and the interval in days between the two labels. The bone formation rate and adjusted apposition rate were calculated according to established formulas (15) and expressed in cubic micrometers per square micrometer per day. The measurement of wall width was performed on the completed remodeling packets following the method of Kragstrup et al. (21). Osteoid width was expressed as the maximum number of lamellae in the osteoid seams for each section. The formation period, resorption period and activation frequency were calculated according to standard formulas (15). These measurements for bone remodeling were performed at 100 magnification. BMD For subjects, BMD was measured at CPMC on Hologic equipment (1000W or QDR4500). For controls, BMD was measured at Helen Hayes Hospital on Lunar equipment. Statistical analysis Statistical analysis was performed using SAS software (SAS Inc., Cary, NC). All data are expressed as mean sem. Patient characteristics were analyzed with descriptive statistics. The significance of differences between the two groups was evaluated by independent two-sided t test. Criterion values were adjusted for unequal variances. The nominal significance level was set at Results Patient characteristics Nine women with idiopathic osteoporosis were compared with 18 healthy control subjects. Subjects and controls did not differ with respect to age, height, weight, body mass index (BMI), or ethnicity (Table 1). The clinical features of this cohort of premenopausal women with idiopathic osteoporosis are shown in Table 2. All women were Caucasian. Most patients were in their early thirties at diagnosis. Age at menarche was normal on average. BMI was normal and did not

3 Donovan et al. Idiopathic Osteoporosis in Premenopausal Women J Clin Endocrinol Metab, June 2005, 90(6): TABLE 1. Baseline characteristics of study population Parameter Controls IOP P Age (yr) BMI (kg/m 2 ) Height (in) Weight (lb) IOP, Idiopathic osteoporosis. differ between patients and controls. All had at least one fragility fracture, and four had sustained a hip fracture. Three were on oral contraceptives, and five were taking calcium at the time of presentation. Three reported a family history of osteoporosis, and one patient reported a positive tobacco history. Mean T-score ( sem) at the lumbar spine in subjects and controls was and , respectively. At the femoral neck, mean T-score ( sem) in subjects and controls was and , respectively. Because these measurements were performed at different times and sites and on equipment from different manufacturers, we did not perform formal statistical analyses. Bone histomorphometry Compared with biopsies of age-, sex-, and race-matched controls, significant differences in bone turnover were identified, particularly in cancellous bone (Table 3 and Fig. 1). None of the patients had osteomalacia. Mean values for cancellous bone volume did not differ significantly between patients and controls. However, a trend toward lower trabecular number and increased trabecular separation was observed in women with idiopathic osteoporosis. In cancellous bone, although there was no increase in osteoid width or perimeter, idiopathic osteoporosis patients had lower parameters of bone formation, including a 10% reduction in wall width, an 18% reduction in mineral apposition rate, and a 42% reduction in mineralized perimeter. Similarly, the bone formation rate was 52% lower, and a trend toward lower activation frequency was observed in the idiopathic osteoporosis patients. There was no statistically significant difference in formation period. Conversely, resorption period TABLE 2. Clinical features of women with idiopathic osteoporosis (n 9) Race (% Caucasian) 100% Age at diagnosis (yr) Age range (yr) Age at menarche (yr) Family history of osteoporosis 33% Ever smokers 14% Current OCP use 33% Current calcium use 56% T-score L-spine Femoral neck Total hip Percent patients with fractures Any site 100 Vertebrae 11 Wrist 11 Hip 44 Rib 11 Other (foot, hand, etc.) 67 OCP, Oral contraceptive pill. was markedly longer and eroded perimeter was increased in the patients. Similarly, wall width and mineralized perimeter were significantly lower in endocortical bone, and resorption period and eroded perimeter were higher in intracortical bone. There were no significant differences in other histomorphometric parameters in cortical bone. Discussion This retrospective study characterizes the histomorphometric features of bone in premenopausal women with unexplained fragility fractures and, in so doing, may provide some insight into the pathophysiology of this disorder. Our results demonstrate that women, like men with idiopathic osteoporosis, have evidence of decreased bone formation. In addition, there is evidence of altered bone resorption. Moreover, our results also suggest that parameters that reflect bone-remodeling activity differ more profoundly from normal than structural parameters. Although retrospective, our results are of interest, because they represent the first histomorphometric data specific to women with idiopathic osteoporosis. The decrease in bone formation we observed is consistent with the work of Khosla et al. (1) who also found evidence of reduced bone formation, as demonstrated by decreased wall thickness, in a group of men and women with idiopathic osteoporosis. In addition to the decrease in wall width, we found significant decreases in other parameters that reflect bone formation, including mineralizing surface, mineral apposition rate, and bone formation rate and a trend toward lower activation frequency. Kurland et al. (7) also reported decreased bone formation and, similar to Khosla et al. (1), lower trabecular volume and cortical width in men with idiopathic osteoporosis. In contrast, we did not find major differences in bone structure such as cancellous bone volume and cortical width. The reasons for the inconsistencies between the structural parameters in our subjects and those reported by Khosla et al. (1) and Kurland et al. (7) are unclear. It is possible that we would have observed structural differences in our study of women with a larger number of subjects or that more sensitive tests of microarchitectural structure, such as microcomputed tomography, would reveal subtle differences in trabecular connectivity between our cases and controls. Like Khosla et al. (1), we found an increase in eroded surface among women with idiopathic osteoporosis and, additionally, demonstrated a longer resorption period. The histomorphometric abnormalities identified in this study were most prominent in cancellous bone. Although many of the fractures occurred at sites that contain a substantial amount of cancellous bone (vertebrae, ribs, distal radius, and proximal femur) (22), others occurred at sites composed predominantly of cortical bone, an observation that differs from other published series. The reasons for this apparent inconsistency are also not clear. We did observe trends in cortical bone similar to those in cancellous bone, suggesting that the disease process also affected cortical bone and may have translated into appendicular fractures as well. With larger numbers of subjects, it is possible that these differences would have attained significance. In addition, we

4 3334 J Clin Endocrinol Metab, June 2005, 90(6): Donovan et al. Idiopathic Osteoporosis in Premenopausal Women TABLE 3. Bone histomorphometric findings in patients with idiopathic osteoporosis (n 9) and controls (n 18) Parameter Controls IOP P Bone structure Cancellous bone volume (%) Cortical porosity (no./sec) Cortical width ( m) Trabecular number (no./mm) Trabecular spacing ( m) Trabecular width ( m) Cancellous bone surface Wall width ( m) Osteoid width (no. lamellae) Osteoid perimeter (%) Mineralized perimeter (%) Mineral apposition rate ( m/d) Bone formation rate ( m/ m 2 d) Formation period (d) Resorption period (d) Eroded perimeter n (%) Activation frequency (cycle/yr) Endocortical surface Wall width ( m) Osteoid width (no. lamellae) Osteoid perimeter (%) Mineralized perimeter (%) Mineral apposition rate ( m/d) Bone formation rate ( m/ m 2 d) Formation period (d) Resorption period (d) Eroded perimeter (%) Activation frequency (cycle/yr) Intracortical surface Wall width ( m) Osteoid width (no. lamellae) Osteoid perimeter (%) Mineralized perimeter (%) Mineral apposition rate ( m/d) Bone formation rate ( m/ m 2 d) Formation period (d) Resorption period (d) Eroded perimeter (%) Activation frequency (cycle/yr) IOP, Idiopathic osteoporosis. would not expect changes at the iliac crest, a non-weightbearing site, to completely reflect those at a true weightbearing site. Because we did not obtain spine radiographs in asymptomatic patients, all prevalent vertebral fractures may not have been identified. Our findings support the notion of a low bone-remodeling state in women with idiopathic osteoporosis. The slightly decreased activation frequency suggests that new remodeling cycles are initiated at a lower rate. Moreover, once a remodeling cycle has been initiated, cells of a given boneremodeling unit appear to spend a larger proportion of time in the resorption period compared with controls, whereas there is no increase in the formation period. Furthermore, during a given formation period, matrix is formed at a lower rate and the osteoid is mineralized more slowly. Thus, in our subjects, the cells of the bone-remodeling unit appear to be less likely to initiate a remodeling cycle, and when they do, osteoblastic function is reduced. The data on eroded surface and resorption period are more difficult to interpret. Increased eroded surface may reflect either a primary increase in osteoclast activity and/or number or a primary decrease in osteoblastic bone formation, such that resorption lacunae excavated in the course of normal osteoclast activity are not refilled. The increased resorption period could also reflect reduced resorptive capacity of individual osteoclasts (23). Thus, the amount of bone resorbed per remodeling cycle may be either the same or increased. However, because there is no increase in the formation period, and a concomitant decrease in osteoblast activity within that period, an imbalance in resorption and formation occurs, and therefore there is net bone loss. Over time, net bone loss could result in lower bone density and fractures. In addition, decreased frequency of remodeling cycles might lead to microdamage accrual that may also predispose to fracture. Thus, idiopathic osteoporosis may represent an uncoupled state in which resorption is increased or normal and formation decreased. Alternatively, idiopathic osteoporosis may represent a state in which activity of both osteoclasts and osteoblasts is reduced. The reasons underlying abnormal remodeling activity in idiopathic osteoporosis are unclear and require further research. The decreased initiation of remodeling cycles, prolonged resorption period, and decreased osteoblastic activity suggest multiple cellular defects in both osteoclasts and os-

5 Donovan et al. Idiopathic Osteoporosis in Premenopausal Women J Clin Endocrinol Metab, June 2005, 90(6): FIG. 1. Characteristics of cancellous bone compared to age-, sex-, and race-matched controls. IOP, Idiopathic osteoporosis. P 0.05 for all parameters. teoblasts that may include 1) defective osteoclast initiation of remodeling cycles, 2) faulty signaling for osteoclasts to undergo apoptosis when resorption is complete, or 3) failure of preosteoblasts to effectively invade resorption cavities, differentiate, or form bone matrix. Genetic factors may be responsible, because several studies have noted a strong family history of osteoporosis in patients with idiopathic osteoporosis (3, 4, 9). Numerous genes and factors may be involved in this coupling process, including TGF-, platelet-derived growth factor, bone morphogenetic proteins, fibroblast growth factors, IGF-I and -II, Wnt, Runx2, osteoprotegerin, receptor activator of nuclear factor- B and its ligand, and leptin among many others. Polymorphisms of candidate genes that have been related to low bone mass in young people include the vitamin D receptor (24), estrogen receptor (25), type I procollagen (26), and IGF-I (27). The potential interactions among these factors are complex, and the abnormalities in individuals with idiopathic osteoporosis may be heterogeneous. In future studies, it may be helpful to investigate the differential expression of these genes/proteins in patients with idiopathic osteoporosis and those with normal bone density. All subjects included in this report had fragility fractures. However, not all sustained fractures at sites typical of postmenopausal women and men with osteoporosis, such as the vertebrae and hip. BMD was not uniformly reduced in all subjects, although it may have been lower than in controls. Moreover, cancellous bone volume and cortical width did not differ significantly between subjects and controls. Thus, these women appear to have an atypical form of osteoporosis, in which abnormal remodeling activity predominates over microarchitectural deterioration. However, the recent definition of osteoporosis as a skeletal disorder characterized by compromised bone strength, predisposing to an increased risk of fracture (28) is not based upon BMD or histomorphometric criteria. Thus, despite the atypical features of this group of women, we felt it reasonable to characterize them as having a form of osteoporosis, albeit different from that seen in older women. This analysis represents a first step in trying to understand the type of bone disease that afflicts these patients. This study has several limitations, related in large part to the retrospective design. The small number of subjects may have limited power to detect between-group differences in microarchitectural parameters. Subject inclusion was based on a history of fragility fracture(s) and exclusion of known secondary causes of osteoporosis, the latter ascertained by chart review of clinical investigations performed earlier; this could have led to inaccurate categorization of subjects included in the study. Given the retrospective design, the specific biochemical investigations performed in each study subject were determined by the clinician involved in the patient s care and were limited by the understanding of secondary causes of osteoporosis and the tests available at the time of

6 3336 J Clin Endocrinol Metab, June 2005, 90(6): Donovan et al. Idiopathic Osteoporosis in Premenopausal Women the original investigations, which spanned a decade. In addition, measurements of PTH, 25-hydroxyvitamin D, and markers of bone formation and resorption, although normal in all subjects, were performed as convenience samples in different laboratories and in some cases by different assays. For these reasons, we are unable to provide meaningful data that might provide clues regarding the pathogenesis of idiopathic osteoporosis. Despite these limitations, however, we believe the results are of significance, as they represent the first histomorphometric analysis performed exclusively in women with idiopathic osteoporosis. Future prospective studies will be needed to confirm our findings and to characterize accurately the pathogenesis of the reduced bone formation in premenopausal women. Acknowledgments Received October 14, Accepted March 10, Address all correspondence and requests for reprints to: Elizabeth Shane, M.D., Columbia University, College of Physicians & Surgeons, Department of Medicine, PH8W-864, 630 West 168th Street, New York, New York. es54@columbia.edu. This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases Grant DK to M.A.D. References 1. Khosla S, Lufkin EG, Hodgson SF, Fitzpatrick LA, Melton III LJ 1994 Epidemiology and clinical features of osteoporosis in young individuals. Bone 15: Moreira Kulak CA, Schussheim DH, McMahon DJ, Kurland E, Silverberg SJ, Siris ES, Bilezikian JP, Shane E 2000 Osteoporosis and low bone mass in premenopausal and perimenopausal women. Endocr Pract 6: Peris P, Guanabens N, Martinez de Osaba MJ, Monegal A, Alvaarez L, Pons F, Ros I, Cerda D, Munoz-Gomez J 2002 Clinical characteristics and etiologic factors of premenopausal osteoporosis in a group of Spanish women. 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