Comparative effectiveness and cardiovascular safety of abaloparatide and teriparatide in postmenopausal women new to anabolic therapy: A US administrative claims database study.

Real-world evidence on the comparative effectiveness and safety of abaloparatide versus teriparatide in women with osteoporosis may help inform treatment decisions. Following 18 months of treatment, abaloparatide was comparable to teriparatide for prevention of nonvertebral fractures, resulted in a 22% risk reduction for hip fractures, and demonstrated similar cardiovascular safety. Osteoporotic fracture risk can be reduced with anabolic or antiresorptive medications. In addition to efficacy and safety data from controlled clinical trials, real-world evidence on comparative effectiveness and safety may help inform treatment decisions. INTRODUCTION: The real-world effectiveness of abaloparatide versus teriparatide on nonvertebral fracture (NVF) incidence and cardiovascular safety during the 19-month period after treatment initiation were evaluated (NCT04974723). METHODS: Anonymized US patient claims data from Symphony Health, Integrated Dataverse (IDV)®, May 1, 2017 to July 31, 2019, included women aged ≥ 50 years with ≥ 1 prescription of abaloparatide or teriparatide and no prior anabolic therapy. Most were enrolled in commercial and Medicare health plans. Index was the date of the initial prescription dispensed during the identification period. In 1:1 propensity score matched cohorts, time to first NVF following index date, major adverse cardiovascular events (MACE), and MACE + heart failure (HF) were compared between cohorts using a Cox proportional hazards model. RESULTS: Propensity score matching yielded 11,616 patients per cohort. Overall median age (interquartile range) was 67 (61, 75) years, and 25.6% had a fracture history. Over 19 months, 335 patients on abaloparatide and 375 on teriparatide had a NVF (hazard ratio [95% confidence interval]: 0.89 [0.77, 1.03]), and 121 and 154 patients, respectively, had a hip fracture [HR (95% CI): 0.78 (0.62, 1.00)]. The MACE and MACE + HF rates were similar between cohorts. CONCLUSIONS: Following 18 months of treatment, abaloparatide was comparable to teriparatide for prevention of NVF and similar cardiovascular safety was demonstrated between cohorts.

Vertebral fracture assessment (VFA) for osteoporosis screening in US postmenopausal women: is it cost-effective?

Vertebral fracture assessment (VFA) is cost-effective when it was incorporated in the routine screening for osteoporosis in community-dwelling women aged ≥ 65 years, which support guidelines, such as the National Osteoporosis Foundation (NOF) for the diagnostic use of VFA as an important addition to fracture risk assessment. INTRODUCTION: To evaluate the cost-effectiveness of VFA as a screening tool to reduce future fracture risk in US community-dwelling women aged ≥ 65 years. METHODS: An individual-level state-transition cost-effectiveness model from a healthcare perspective was constructed using derived data from published literature. The time horizon was lifetime. Five screening strategies were compared, including no screening at all, central dual-energy X-ray absorptiometry (DXA) only, VFA only, central DXA followed by VFA if the femoral neck T-score (FN-T) ≤ - 1.5, or if the FN-T ≤ - 1.0. Various initiation ages and rescreening intervals were evaluated. Oral bisphosphonate treatment for 5-year periods was assumed. Incremental cost-effectiveness ratios (2017 US dollars per quality-adjusted life-year (QALY) gained) were used as the outcome measure. RESULTS: The incorporation of VFA slightly increased life expectancy by 0.1 years and reduced the number of subsequent osteoporotic fractures by 3.7% and 7.7% compared with using DXA alone and no screening, respectively, leading to approximately 30 billion dollars saved. Regardless of initiation ages and rescreening intervals, central DXA followed by VFA if the FN-T ≤ - 1.0 was most cost-effective ($40,792 per QALY when the screening is initiated at age 65 years and with rescreening every 5 years). Results were robust to change in VF incidence and medication costs. CONCLUSION: In women aged ≥ 65 years, VFA is cost-effective when it was incorporated in routine screening for osteoporosis. Our findings support the National Osteoporosis Foundation (NOF) guidelines for the diagnostic use of VFA as an important addition to fracture risk assessment.

Abaloparatide effect on forearm bone mineral density and wrist fracture risk in postmenopausal women with osteoporosis.

PURPOSE: Wrist fractures are common, contribute significantly to morbidity in women with postmenopausal osteoporosis, and occur predominantly at the ultradistal radius, a site rich in trabecular bone. This exploratory analysis of the phase 3 ACTIVE study evaluated effects of abaloparatide versus placebo and teriparatide on forearm bone mineral density (BMD) and risk of wrist fracture. METHODS: Forearm BMD was measured by dual energy X-ray absorptiometry in a subset of 982 women from ACTIVE, evenly distributed across the three treatment groups. Wrist fractures were ascertained in the total cohort (N = 2463). RESULTS: After 18 months, ultradistal radius BMD changes from baseline were 2.25 percentage points greater for abaloparatide compared with placebo (95% confidence interval (CI) 1.38, 3.12, p < 0.001) and 1.54 percentage points greater for abaloparatide compared with teriparatide (95% CI 0.64, 2.45, p < 0.001). At 18 months, 1/3 radius BMD losses (versus baseline) were similar for abaloparatide compared with placebo (-0.42; 95% CI -1.03, 0.20; p = 0.19) but losses with teriparatide exceeded those of placebo (-1.66%; 95% CI -2.27, -1.06; p < 0.001). The decline with abaloparatide was less than that seen with teriparatide (group difference 1.22%; 95% CI 0.57, 1.87; p < 0.001). The radius BMD findings, at both ultradistal and 1/3 sites, are consistent with the numerically lower incidence of wrist fractures observed in women treated with abaloparatide compared with teriparatide (HR = 0.43; 95% CI 0.18, 1.03; p = 0.052) and placebo (HR = 0.49, 95% CI 0.20, 1.19, p = 0.11). CONCLUSIONS: Compared with teriparatide, abaloparatide increased BMD at the ultradistal radius (primarily trabecular bone) and decreased BMD to a lesser extent at the 1/3 radius (primarily cortical bone), likely contributing to the numerically lower wrist fracture incidence observed with abaloparatide.

Determinants of bone mass and bone size in a large cohort of physically active young adult men.

The determinants of bone mineral density (BMD) at multiple sites were examined in a fit college population. Subjects were 755 males (mean age = 18.7 years) entering the United States Military Academy. A questionnaire assessed exercise frequency and milk, caffeine, and alcohol consumption and tobacco use. Academy staff measured height, weight, and fitness. Calcaneal BMD was measured by peripheral dual-energy x-ray absorptiometry (pDXA). Peripheral-quantitative computed tomography (pQCT) was used to measure tibial mineral content, circumference and cortical thickness. Spine and hip BMD were measured by DXA in a subset (n = 159). Mean BMD at all sites was approximately one standard deviation above young normal (p < 0.05). African Americans had significantly higher hip, spine and heel BMD and greater tibial mineral content and cortical thickness than Caucasians and Asians. In Caucasians (n = 653), weight was a significant determinant of BMD at every skeletal site. Prior exercise levels and milk intake positively related to bone density and size, while caffeine had a negative impact. There was an apparent interaction between milk and exercise in BMD at the heel, spine, hip and tibial mineral content and cortical thickness. Our data confirm the importance of race, body size, milk intake and duration of weekly exercise as determinants of BMD and bone size.

Short-term effects of estrogen, tamoxifen and raloxifene on hemostasis: a randomized-controlled study and review of the literature.

INTRODUCTION: Estrogen therapy (ET), tamoxifen and raloxifene are associated with a two- to three-fold increased risk of venous thrombosis (VT); however, the mechanisms by which each drug increases venous thrombosis propensity are not fully understood. The objectives of this investigation were to compare the effects of these three treatments on hemostasis in a head to head randomized placebo-controlled trial. PATIENTS/METHODS: Ninety-four postmenopausal women were assigned to receive oral estrogen (conjugated equine estrogen [CEE] 0.625 mg, n=23), tamoxifen 20 mg (n=24), raloxifene 60 mg (n=24) or placebo (n=23) daily for 6 months. Blood samples were analyzed for procoagulant factors (prothrombin, factors VII [fVII], VIII [fVIII], IX [fIX] and XI [fXI], D-dimer and von Willebrand factor [vWf]), anticoagulant factors (antithrombin [AT], total and free protein S, protein C and activated protein C [APC] resistance) and fibrinolytic factors (thrombin activatable fibrinolysis inhibitor [TAFI] and plasminogen activator inhibitor-1 [PAI-1]), at baseline and at 6 months of treatment. RESULTS: Estrogen increased factor VII and D-dimer, and decreased antithrombin, total and free protein S and PAI-1. Changes with tamoxifen were distinct from estrogen with increases in factors VIII, IX, vWf and free protein S, and decreases in AT, total protein S, protein C and plasminogen activator inhibitor-1. Raloxifene produced similar effects as tamoxifen, but did not increase factor IX or decrease protein C. CONCLUSIONS: Estrogen, tamoxifen and raloxifene affected hemostasis favoring procoagulation and impairing anticoagulation. The biochemical effects of the selective estrogen receptor modulators (SERMs) were distinct from those of estrogen and differed only subtly from each other.

Constant mineralization density distribution in cancellous human bone.

The degree of mineralization of bone matrix is an important factor in determining the mechanical competence of bone. The remodeling and modeling activities of bone cells together with the time course of mineralization of newly formed bone matrix generate a characteristic bone mineralization density distribution (BMDD). In this study we investigated the biological variance of the BMDD at the micrometer level, applying a quantitative backscattered electron imaging (qBEI) method. We used the mean calcium concentration (Ca(Mean)), the most frequent calcium concentration (Ca(Peak)), and full width at half maximum (Ca(Width)) to characterize the BMDD. In none of the BMDD parameters were statistically significant differences found due to ethnicity (15 African-American vs. 27 Caucasian premenopausal women), skeletal site variance (20 ilium, 24 vertebral body, 13 patella, 13 femoral neck, and 13 femoral head), age (25 to 95 years), or gender. Additionally, the interindividual variance of Ca(Mean) and Ca(Peak), irrespective of biological factors, was found to be remarkably small (SD < 2.1% of means). However, there are significant changes in the BMDD in the case of bone diseases (e.g., osteomalacia) or following clinical treatment (e.g., alendronate). From the lack of intraindividual changes among different skeletal sites we conclude that diagnostic transiliac biopsies can be used to determine the BMDD variables of cancellous bone for the entire skeleton of the patient. In order to quantify deviations from normal mineralization, a reference BMDD for adult humans was calculated using bone samples from 52 individuals. Because we find the BMDD to be essentially constant in healthy adult humans, qBEI provides a sensitive means to detect even small changes in mineralization due to bone disease or therapeutic intervention.

Cytokine profile in patients with multiple sclerosis following vitamin D supplementation.

Multiple sclerosis (MS) patients were randomized, in a double blind design, and placed into either a vitamin D supplemented group or a placebo control group. As expected, serum 25-hydroxyvitamin D levels increased significantly following 6 month vitamin D supplementation (17+/-6 ng/ml at baseline to 28+/-8 ng/ml at 6 months). Vitamin D supplementation also significantly increased serum transforming growth factor (TGF)-beta 1 levels from 230+/-21 pg/ml at baseline to 295+/-40 pg/ml 6 months later. Placebo treatment had no effect on serum TGF-beta 1 levels. Tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-13 were not different following vitamin D supplementation. IL-2 mRNA levels decreased following vitamin D supplementation but the differences did not reach significance. Vitamin D supplementation of MS patients for 6 months was associated with increased vitamin D status and serum TGF-beta 1.

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.

Is parathyroid hormone a therapeutic option for osteoporosis? A review of the clinical evidence.

Most of the data on the anabolic effect of PTH have been obtained with hPTH(1-34). Studies have shown a marked increment in spinal bone mass. Most recently we have shown that PTH and estrogen can be given together where there is increased total bone mineral and no loss of bone at any skeletal site. We have also shown the first reduction in vertebral deformity incidence due to PTH treatment.

Alendronate does not block the anabolic effect of PTH in postmenopausal osteoporotic women.

In rodent osteoporosis models, anabolic activity of parathyroid hormone (PTH) is preserved in the presence of antiresorptive agents. Anabolic activity is also preserved when PTH is administered to estrogenized postmenopausal women. In contrast, in the ewe treated with tiludronate, PTH-induced stimulation of bone turnover did not occur. To determine whether PTH in combination with alendronate could be a viable treatment for osteoporosis, we performed a short-term study of postmenopausal women with osteoporosis (n = 10) already on alendronate 10 mg/day to determine whether PTH could increase bone formation assessed biochemically. Patients continued alendronate alone (n = 5) or continued alendronate with 400 IU/day subcutaneous human PTH (1-34) added for 6 weeks. Subjects receiving PTH had serum and urine sampling weekly during PTH treatment and for 5 weeks thereafter. Sampling was performed approximately biweekly for subjects who had been on alendronate alone for 11 weeks. Samples were analyzed for osteocalcin (OC), propeptide of type I procollagen (PICP), bone-specific alkaline phosphatase (BSAP), cross-linked urinary N-telopeptide (NTX), and free urinary pyridinoline (PYD). Markers of bone formation increased within 3 weeks in the PTH plus alendronate group, with mean peak levels at 5-7 weeks: OC 49%, p < 0.01; PICP 61%, p < 0.01; and BSAP 24%, p = 0.12. Levels returned to baseline after discontinuing PTH, with PICP declining the most rapidly. There were no significant changes at any time in the alendronate alone group. There were no increments in either urinary NTX or PYD in either treatment group throughout the observation period. The bone turnover marker changes seen with PTH plus alendronate were similar to those seen with PTH plus hormone replacement. These data suggest that: PTH can stimulate bone formation, evidenced by elevations of bone formation markers, even in the presence of a potent bisphosphonate; in the presence of alendronate, PTH-stimulated bone formation precedes stimulation of bone resorption, suggesting that PTH stimulates bone formation de novo; and the combination of PTH and alendronate may be a viable treatment option for postmenopausal women with osteoporosis.

Bone mass and vitamin D deficiency in adults with advanced cystic fibrosis lung disease.

Osteoporosis and fractures are increasingly recognized in children and adults with cystic fibrosis. To investigate the prevalence and pathogenesis of osteoporosis and low bone mass in adults with advanced pulmonary disease due to cystic fibrosis, we examined the relationships between bone mineral density (BMD), anthropomorphic variables, pulmonary status, glucocorticoid therapy, and vitamin D concentrations. BMD of the lumbar spine, hip, and proximal radius was measured by dual energy X-ray absorptiometry in 30 white adults (16 women), age 30 +/- 2 yr (mean +/- SEM). Compared with a normal control population, the patients had significantly reduced BMD at the lumbar spine (17 +/- 3%), total hip and femoral neck (24 +/- 3% and 20 +/- 4%, respectively). The radius was significantly less demineralized (4 +/- 2%; p <= 0.003) than the other sites. Moreover, only 21% of patients with cystic fibrosis had normal BMD (T score > -1.0) at the lumbar spine, 23% at the hip sites, and 39% at the radius. Age, weight, and body mass index (BMI) were most strongly correlated with bone mass, whereas glucocorticoid therapy and pulmonary function were not predictive. Despite oral vitamin D (400 to 800 IU daily), the mean serum 25-hydroxyvitamin D (25-OHD) concentration was at the low end of the normal range (16 +/- 2 ng/ml; normal 10 to 52 ng/ml); 8 of 20 patients (40%) had frankly low (<= 10 ng/ml) levels. BMD was significantly lower in patients with low 25-OHD concentrations at the lumbar spine (0.774 +/- 0.02 versus 0.913 +/- 0.04 g/cm2; p = 0.01) and total hip (0.648 +/- 0.04 versus 0.811 +/- 0.04 g/cm2; p = 0.01). Vertebral fractures were present in 19% of subjects and 41% had a confirmed history of previous fracture. In summary, osteoporosis, low bone mass, and fractures are common in adults with advanced cystic fibrosis lung disease. Despite oral supplements, vitamin D deficiency is also common and is associated with more severe demineralization at the lumbar spine and hip. We conclude that the widespread practice of oral supplementation with 400 to 800 units of vitamin D is ineffective in maintaining normal vitamin D stores in many patients with cystic fibrosis. To ensure adequacy of vitamin D stores, measurement of serum 25-OHD should be included in the routine management of patients with cystic fibrosis.

Parathyroid responsivity in postmenopausal women with osteoporosis during treatment with parathyroid hormone.

Endocrine systems may be affected permanently by administration of supraphysiologic doses of hormone. This is a well known complication of glucocorticoid treatment where the pituitary/adrenal axis may never fully recover, especially when large doses of steroids are needed during significant physical stress. The goal of this investigation was to determine whether responsivity of the parathyroid gland was normal after use of (1-34)PTH daily as an investigational therapy for osteoporosis. Patients were all postmenopausal osteoporotic women treated with estrogen and enrolled in a 3-yr trial of (1-34)PTH by daily subcutaneous injection (400 IU/day) in addition to their estrogen therapy. A volunteer subgroup (n = 10) of this population was recruited for this investigation. All patients had an EDTA-provoked hypocalcemic challenge before beginning PTH treatment. The same patients had repeat EDTA-challenge tests at various times during the 3-yr PTH treatment trial. Three patients had 2 infusions while on PTH treatment (interim and at the end of 3 yr). Ionized calcium declined identically before and during PTH treatment in response to the EDTA stimulus. PTH(1-84) responses were identical before and during PTH therapy. Furthermore, there were no differences in 1,25(OH)2D elevation or in phosphorus reduction over the course of the EDTA infusion during daily PTH treatment. Osteocalcin levels were higher during PTH treatment, as expected, but responsivity to acute endogenous PTH elevations was the same after PTH treatment. We conclude that 1-34PTH therapy, at 400 IU/day for up to 3 yr, does not suppress parathyroid responsivity and should therefore (at least within this period of treatment) have no permanent adverse effect on the ability of the body to maintain calcium homeostasis. Additionally, there is no difference in target organ responsivity to acute endogenous elevations of PTH after exogenous PTH therapy.

Calcium potentiates the effect of estrogen and calcitonin on bone mass: review and analysis.

We reviewed published clinical trials that measured bone mass of postmenopausal women from at least one skeletal site to evaluate whether calcium supplementation influenced the efficacy of estrogens and intranasal calcitonin on bone mass change. We compared results of the administration of oral estrogen or nasal calcitonin in conjuction with additional calcium intake either through diet or supplements compared with those of estrogen or calcitonin alone. Of the 31 published estrogen trials analyzed, 20 modified the diet or used a calcium supplement (total 1183 mg/d) and 11 did not (total 563 mg/d). The mean increase in bone mass of the lumbar spine when estrogen was given alone was 1.3%/y (n = 5) compared with 3.3%/y when estrogen was given in conjunction with calcium (n = 14; P = 0.01). The mean increase in bone mass of the femoral neck with estrogen alone (n = 3) was only 0.9%/y compared with 2.4%/y when calcium was given with estrogen (n = 6; P = 0.04). Similarly, forearm bone mass increased 0.4%/y with estrogen alone (n = 7) compared with 2.1%/y when estrogen was given with calcium (n = 12; P = 0.04). Similar results were found when weighted means were calculated. Of the seven published trials evaluating the effects of 200 IU nasal salmon calcitonin, six also used calcium supplements (total 1466 mg/d) whereas one used calcitonin alone (total 627 mg/d). Bone mass of the lumbar spine increased 2.1% with calcitonin plus calcium supplementation compared with -0.2%/y with calcitonin alone. These results suggest that a high calcium intake potentiates the positive effect of estrogen on bone mass at all skeletal sites and perhaps that of calcitonin on bone mass of the spine.

Insulin-like growth factor-I in men with idiopathic osteoporosis.

The etiology of osteoporosis in most men without a history of alcohol abuse, hypogonadism, or glucocorticoid excess is unknown. Several histomorphometric reports have demonstrated a reduction in indices of bone formation. We tested the hypothesis that the putative reduction in bone formation in men with idiopathic osteoporosis may be related to deficiencies in skeletal mechanisms that are mediated by insulin-like growth factor I (IGF-I). Twenty-four middle-aged men (50.5 +/- 1.9 yr) with severe idiopathic osteoporosis (mean lumbar spine T-score -3.5 +/- 0.16) were studied. The following biochemical indices were all normal: serum calcium, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, testosterone, osteocalcin, carboxyterminal propeptide of type I collagen, bone specific alkaline phosphatase, urinary calcium, and collagen crosslinks. Parathyroid hormone level was in the lower range of normal, 25 +/- 2 pg/mL (nl: 10-65). Mean serum IGF-I level was also in the lower range of normal, 157.9 +/- 7.6 ng/mL (normal age-matched range, 140-260 ng/mL). Eight men had IGF-I levels that were below 140 ng/mL. The mean IGF-IZ score was -0.75, significantly different from the expected mean of zero (P = 0.0002). IGF-I was correlated negatively with age (r = -0.49, P < 0.02). With age held constant, serum IGF-I accounted for 15% of the variance in lumbar bone mineral density (BMD; P < 0.001). The osteocalcin concentration correlated well with bone density at the distal 1/3 radius (r = +0.44; P < 0.002). Histomorphometric analysis of bone biopsy specimens showed significant reductions in cancellous bone volume (31%; P < 0.001), cortical width (28%; P < 0.05), osteoid surface (33%; P < 0.01), and bone formation rate (54%; P < 0.01) when results were compared with age-matched control subjects. Percent eroded surface was normal and was correlated inversely with serum IGF-I levels (r = -0.5; P < 0.04). These results suggest that serum IGF-I levels are reduced in men with idiopathic osteoporosis and that IGF-I correlates with and may contribute to the reduction in lumbar spine bone mass density (BMD). The low IGF-I levels may reflect the reduction in bone formation demonstrated by histomorphometry. Insights into the etiology of idiopathic osteoporosis in men may be revealed by further studies of the IGF-I axis.

Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis.

BACKGROUND: Small increases in bone mass are commonly seen with existing treatments for osteoporosis, which reduce bone remodelling and primarily prevent bone loss. Since these drugs reduce but do not eliminate risk of fractures, an anabolic agent that would increase bone mass and potentially cure the underlying skeletal problem is needed. METHODS: We did a 3-year randomised controlled trial to find out the effects of 1-34 human parathyroid hormone (hPTH [1-34], 400 U/25 micrograms daily subcutaneously) in postmenopausal women with osteoporosis taking hormone-replacement therapy (n = 17). The controls were women taking hormone-replacement therapy only (n = 17). The primary outcome was bone-mineral density of the lumbar vertebrae, with bone-mineral density at other sites and vertebral fractures as secondary endpoints. FINDINGS: Patients taking hormone-replacement therapy and PTH (1-34) had continuous increase in vertebral bone-mineral density during the 3 years, whereas there was no significant change in the control group. The total increase in vertebral bone-mineral density was 13.0% (p < 0.001); 2.7% at the hip (p = 0.05); and 8.0% in total-body bone mineral (p = 0.002). No loss of bone mass was found at any skeletal site. Increased bone mass was associated with a reduction in the rate of vertebral fractures, which was significant when fractures were taken as a 15% reduction in vertebral height (p = 0.04). During the first 6 months of treatment, serum osteocalcin concentration, which reflects bone formation, increased by more than 55%, whereas excretion of crosslinked n-telopeptide, which reflects bone resorption, increased by only 20%, which suggests some uncoupling of bone formation and resorption. By 6 months, there were similar increases in both markers, which gradually returned towards baseline as the study progressed. Vertebral bone-mineral density increased most during the first year of PTH treatment. INTERPRETATION: We found that PTH has a pronouned anabolic effect on the central skeleton in patients on hormone-replacement therapy. PTH also increases total-body bone mineral, with no detrimental effects at any skeletal site. The increased vertebral mass was associated with a reduced rate of vertebral fracture, despite increased bone turnover. Bone-mass changes may be consistent with a reduction in all osteoporotic fractures. If confirmed in larger studies, these data have important implications for the treatment of postmenopausal osteoporosis.

Histomorphometric assessment of bone mass, structure, and remodeling: a comparison between healthy black and white premenopausal women.

While noninvasive studies of bone mass and turnover in blacks and whites abound, histologic evaluations are very rare. We have performed a comparative bone histomorphometric study of iliac biopsies from 55 healthy, premenopausal women including 21 blacks (mean age 33.4 + 1.2 years) and 34 whites (mean age 32.5 + 0.8 years) of comparable age, weight, body composition, education, and lifestyle. Biochemical indices of mineral metabolism: parathyroid hormone, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, serum ionized calcium, serum phosphorus, and urinary calcium/creatinine were measured in the fasting state. Blacks had lower 25-hydroxyvitamin D (315 +/- 3.36 vs. 63.21 +/- 3.79 nmol/l, p = 0.0001). Histomorphometric indices of bone volume, structure, and connectivity were not different between groups. The following indices of bone remodeling were also similar in both groups: eroded perimeter, osteoid width, mineralizing perimeter, tissue-based bone formation rate, osteoid maturation time, active formation period, and activation frequency. However, osteoid perimeter (black [B] = 15.85 +/- 1.30 vs. white [W] = 9.49 +/- 0.70%, p = 0.0002), osteoid area (B = 2.55 +/- 0.32 vs. W = 1.39 +/- 0.12%, p = 0.003), single-labeled perimeter (B = 5.46 +/- 0.54 vs. W = 4.04 +/- 0.33%, p = 0.03), mineralization lag time (B = 38.18 +/- 4.04 vs. W = 21.83 +/- 1.60 days, p < 0.009), and total formation period (B = 148.15 +/- 19.70 vs. W = 84.04 +/- 7.62 days, p = 0.0056) were higher in blacks than in whites. The quiescent perimeter (B = 76.91 +/- 1.40 vs. W = 84.25 +/- 0.91%, p = 0.0001), mineral apposition rate (B = 0.70 +/- 0.02 vs. W = 0.75 +/- 0.02 micron/day, p = 0.066), mineralizing osteoid perimeter (B = 0.49 +/- 0.04 vs. W = 0.75 +/- 0.04%, p = 0.0001) and adjusted apposition rate (B = 0.35 +/- 0.04 vs. W = 0.58 +/- 0.04 micron3/micron2/day, p = 0.0001) were all lower in blacks than in whites. These results indicate that there are no differences in bone volume, microstructure, or turnover between black and white premenopausal women. However, there are significant differences in the mechanism of bone formation between the two groups, with a lower rate of mineralized matrix apposition within each remodeling unit and a longer total formation period in blacks than in whites. The differences appear to the result of more frequent and/or longer inactive periods in the life span of the bone formation units in blacks. These differences may allow a greater overall deposition of bone mineral in black women and therefore help explain a higher bone mass and perhaps better bone quality in black than white women.

Resistance to bone resorbing effects of PTH in black women.

Black women have a lower incidence of vertebral and hip fractures than white women, possibly due to differences in skeletal and mineral metabolism. One suggested mechanism is that blacks have decreased skeletal sensitivity to parathyroid hormone (PTH). To test this hypothesis, we infused h(1-34)PTH in healthy premenopausal black (n = 15) and white (n = 18) women over 24 h and measured serum and urine indices of bone turnover and calcium metabolism throughout the infusion. At baseline, the mean 25-hydroxyvitamin D (25(OH)D) concentration was significantly lower in black women (46%). There were also nearly significant trends toward higher PTH and lower urinary calcium and pyridinoline levels in black women. During infusion, there were no racial differences in the mean (1-34)PTH levels achieved or in resultant elevations of serum calcium or 1,25-dihydroxyvitamin D (1,25(OH)2D) levels. Endogenous parathyroid suppression (measured by (1-84)PTH levels) was also similar between blacks and whites. There was an initial decline in urinary calcium/creatinine in both groups with a greater reduction in black women early in the infusion period (p < 0.05 at 8 h). Furthermore, blacks had lower levels of urinary calcium/creatinine throughout the infusion (p < 0.05 group difference). Bone formation markers (carboxy-terminal propeptide of type I procollagen and osteocalcin) decreased within 8 h and continued to decline throughout the infusion with no distinguishable racial differences (p < 0.05 time trend for both). The most dramatic difference between black and white women in response to PTH infusion was represented by the bone resorption markers. Three separate metabolites of bone resorption (cross-linked N-telopeptide of type I collagen, cross-linked C-telopeptide of type I collagen, and free pyridinoline) all showed substantially greater elevations in white (mean peak increments 399, 725, and 43%) compared with black women (mean peak increments 317, 369, and 17%) during the infusion (p < 0.05 group differences for all three variables). These data strongly suggest that blacks have decreased skeletal sensitivity to the acute resorptive effects of increased PTH. This finding indicates that calcium homeostasis may be accomplished in blacks (during times of relative calcium deficiency) by greater conservation of calcium from nonskeletal sources (most likely renal) with relative preservation of skeletal tissue. These differences in calcium economy could account, at least in part, for the increased bone mass and lower incidence of osteoporotic fractures in black women.

Bone density change and biochemical indices of skeletal turnover.

Although biochemical markers of skeletal turnover cannot replace bone density scanning for the diagnosis of osteoporosis, it is thought that they may help add to prediction of fracture risk and help determine adequacy of osteoporosis therapy. Nevertheless, whether biochemical markers in the serum or urine can predict individual rates of bone loss in the spine or hip region is unknown. We studied a heterogeneous group of women (n = 81) who were premenopausal, untreated postmenopausal, and estrogen-treated postmenopausal with baseline determination of body mass index (BMI), calcium intake, biochemical measurements, and serial bone densitometry over 3 years. Serum assays included bone Gla protein (BGP), total and bone-specific alkaline phosphatase (AP, BSAP), carboxyterminal propeptide of type I procollagen (PICP), carboxyterminal telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase (TRAP). Urine assays included hydroxyproline (OHP), calcium, total pyridinoline, and total deoxypyridinoline. Individual biochemical markers and calcium intake were modestly correlated with bone density changes but were inconsistent regarding the spine versus the hip. All of the formation variables were significantly correlated to spine density change (r = -0.24 to -0.49) whereas the only resorption variable that correlated was urine OHp/Cr (r = -0.31). The only formation variable that correlated with hip density change was serum PICP whereas all of the resorption variables except serum TRAP were correlated (r = -0.23 to -0.35). "High turnover" individuals were defined at those with levels of biochemical variables at least 1 SD above the mean young normal for each variable. Higher bone loss rates were seen in this group for several of the turnover markers compared with bone loss rates in all other individuals. However, the sensitivity of this "high turnover" status for identifying high bone losers did not exceed 60% for any of the variables. In untreated postmenopausal women, a model using urine OHp, serum ICTP, serum BSAP, and calcium intake was able to predict 42% of the variance of change in BMD of the lumbar spine. A model using BMI, serum ICTP, and serum BGP could predict 32% of the variance of change in BMD of the femoral neck. No combination of markers could predict variance in bone density change at either site in estrogenized women (premenopausal and estrogen-treated postmenopausal). We conclude that measuring individual serum and urine markers of bone turnover cannot accurately predict bone loss rates in the spine and hip; however, combinations of demographic and biochemical variables could predict some of the variance in untreated postmenopausal women. Biochemical markers cannot replace serial bone densitometry for accurate determination of change in bone mass at the most clinically relevant sites.