CXCL5 stimulation of RANK ligand expression in Paget's disease of bone.

Paget's disease of bone (PDB) is a chronic focal skeletal disorder that affects 2-3% of the population over 55 years of age. PDB is marked by highly localized areas of bone turnover with increased osteoclast activity. Evidence suggests a functional role for measles virus nucleocapsid protein (MVNP) in the pathogenesis of PDB. In the present study, we identified elevated levels (≈ 180-fold) of CXCL5 mRNA expression in bone marrow cells from patients with PDB compared with that in normal subjects. In addition, CXCL5 levels are increased (five-fold) in serum samples from patients with PDB. Furthermore, MVNP transduction in human bone marrow monocytes significantly increased CXCL5 mRNA expression. Real-time PCR analysis showed that CXCL5 stimulation increased (6.8-fold) RANKL mRNA expression in normal human bone marrow-derived stromal (SAKA-T) cells. Moreover, CXCL5 increased (5.2-fold) CXCR1 receptor expression in these cells. We further showed that CXCL5 treatment elevated the expression levels of phospho-ERK1/2 and phospho-p38. CXCL5 also significantly increased phosphorylation of CREB (cAMP response element-binding) in bone marrow stromal/preosteoblast cells. Chromatin immuneprecipitation (ChIP) assay confirmed phospho-CREB binding to RANKL gene promoter region. Further, the suppression of p-CREB expression by the inhibitors of ERK1/2, p38 and PKA significantly decreased CXCL5 stimulation of hRANKL gene promoter activity. Thus, our results suggest that CREB is a downstream effector of CXCL5 signaling and that increased levels of CXCL5 contribute to enhanced levels of RANKL expression in PDB.

The effect of endogenous parathyroid hormone in iliac bone structure and turnover in healthy postmenopausal women.

Little is known about the effect of endogenous parathyroid hormone (PTH) on the skeleton in postmenopausal women without hyperparathyroidism. In this study, the effects of PTH on bone were investigated in iliac crest biopsies obtained from 37 healthy white postmenopausal women aged 50-73 years. The results showed that neither cancellous nor cortical bone structure changed with serum PTH levels. In cancellous bone, bone formation (wall thickness, osteoid surface, osteoblast surface, mineralizing surface, and mineral apposition rate) and turnover (bone formation rate at the surface, volume levels, and activation frequency) variables increased with increasing serum PTH levels (all p < 0.05) in univariate analysis. Multiple linear regressions, adjusted for serum 25-OHD, calcium, alkaline phosphatase, age, and BMI, showed that serum PTH level was independently associated with wall thickness, osteoid surface, osteoblast surface, mineralizing surface, and bone formation rate (all p < 0.05). In cortical bone, no histomorphometric variable was correlated with PTH levels. On the endosteal surface, some of the bone formation (osteoid surface, osteoblast surface, mineralizing surface) and turnover (bone formation rate at the bone surface levels and activation frequency) variables were positively correlated with PTH levels (all p < 0.05). None of these variables could be independently predicted by PTH status. We conclude that in healthy postmenopausal women endogenous PTH has a positive effect on bone formation on the cancellous surface. The effects of PTH on the endosteal surface are probably confounded by other factors.

Calcium and vitamin D in sarcoidosis: how to assess and manage.

The synthesis of vitamin D is altered by the granulomatous inflammation of sarcoidosis leading to increased production of 1, 25-dihydroxyvitamin D. Mounting evidence suggests that vitamin D is an immunomodulating hormone that inhibits both antigen presentation by cells of the innate immune system, and the cytokine release and proliferation of Th1 cells. These and other extraskeletal health benefits have led to an increase in vitamin D assessment and pharmacological supplementation in the general population. This review highlights the altered synthesis and general immunomodulating properties of vitamin D with a special emphasis on known interactions with sarcoidosis. In addition, the assessment of vitamin D nutritional status, its pharmacological supplementation, and the management of bone health in patients with sarcoidosis are reviewed.

Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop.

OBJECTIVE: Asymptomatic primary hyperparathyroidism (PHPT) is a common clinical problem. The purpose of this report is to guide the use of diagnostic tests for this condition in clinical practice. PARTICIPANTS: Interested professional societies selected a representative for the consensus committee and provided funding for a one-day meeting. A subgroup of this committee set the program and developed key questions for review. Consensus was established at a closed meeting that followed. The conclusions were then circulated to the participating professional societies. EVIDENCE: Each question was addressed by a relevant literature search (on PubMed), and the data were presented for discussion at the group meeting. CONSENSUS PROCESS: Consensus was achieved by a group meeting. Statements were prepared by all authors, with comments relating to accuracy from the diagnosis subgroup and by representatives from the participating professional societies. CONCLUSIONS: We conclude that: 1) reference ranges should be established for serum PTH in vitamin D-replete healthy individuals; 2) second- and third-generation PTH assays are both helpful in the diagnosis of PHPT; 3) DNA sequence testing can be useful in familial hyperparathyroidism or hypercalcemia; 4) normocalcemic PHPT is a variant of the more common presentation of PHPT with hypercalcemia; 5) serum 25-hydroxyvitamin D levels should be measured and, if vitamin D insufficiency is present, it should be treated as part of any management course; and 6) the estimated glomerular filtration rate should be used to determine the level of kidney function in PHPT: an estimated glomerular filtration rate of less than 60 ml/min.1.73 m2 should be a benchmark for decisions about surgery in established asymptomatic PHPT.

Osteoclast inhibitory peptide-1 (OIP-1) inhibits measles virus nucleocapsid protein stimulated osteoclast formation/activity.

Paget's disease (PD) of bone is characterized by increased activity of large abnormal osteoclasts (OCLs) which contain paramyxoviral nuclear and cytoplasmic inclusions. MVNP gene expression has been shown to induce pagetic phenotype in OCLs. We previously characterized the osteoclast inhibitory peptide-1 (OIP-1/hSca) which inhibits OCL formation/bone resorption. OIP-1 is a glycophosphatidylinositol (GPI)-linked membrane protein containing a 79 amino acid extra cellular peptide and a 32 amino acid carboxy terminal GPI-linked peptide (c-peptide) which is critical for OCL inhibition. In this study, we demonstrate that OIP-1 c-peptide significantly decreased (43%) osteoclast differentiation of peripheral blood mononuclear cells from patients with PD. Also, OIP-1 treatment to normal human bone marrow mononuclear cells transduced with the MVNP inhibited (41%) osteoclast precursor (CFU-GM) growth in methyl-cellulose cultures. We further tested if OIP-1 overexpression in the OCL lineage in transgenic mice inhibits MVNP stimulated OCL formation. MVNP transduction and RANKL stimulation of OIP-1 mouse bone marrow cells showed a significant decrease (43%) in OCL formation and inhibition (38%) of bone resorption area compared to wild-type mice. Western blot analysis identified that OIP-1 decreased (3.5-fold) MVNP induced TRAF2 expression during OCL differentiation. MVNP or OIP-1 expression did not affect TRAF6 levels. Furthermore, OIP-1 expression resulted in a significant inhibition of MVNP stimulated ASK1, Rac1, c-Fos, p-JNK, and NFATc1 expression during OCL differentiation. These results suggest that OIP-1 inhibits MVNP induced pagetic OCL formation/activity through suppression of RANK signaling. Thus, OIP-1 may have therapeutic utility against excess bone resorption in patients with PD.

Cancellous bone lamellae strongly affect microcrack propagation and apparent mechanical properties: separation of patients with osteoporotic fracture from normal controls using a 2D nonlinear finite element method (biomechanical stereology).

Biomechanical stereology is proposed as a two-dimensional (2D) finite element (FE) method to estimate the ability of bone tissue to sustain damage and to separate patients with osteoporotic fracture from normal controls. Briefly, 2D nonlinear compact tension FE models were created from quantitative back scattered electron images taken of iliac crest bone specimens collected from the individuals with or without osteoporotic fracture history. The effects of bone mineral microstructure on predicted bone fracture toughness and microcrack propagation were examined. The 2D FE models were used as surrogates for the real bone tissues. The calculated microcrack propagation results and bone mechanical properties were examined as surrogates for measurements from mechanical testing of actual specimens. The results for the 2D FE simulation separated patients with osteoporotic fracture from normal controls even though only the variability in tissue mineral microstructure was used to build the models. The models were deliberately created to ignore all differences in mean mineralization. Hence, the current results support the following hypotheses: (1) that material heterogeneity is important to the separation of patients with osteoporotic fracture from normal controls; and (2) that 2D nonlinear finite element modeling can produce surrogate mechanical parameters that separate patients with fracture from normal controls.

Very low or undetectable intact parathyroid hormone levels in patients with surgically verified parathyroid adenomas.

OBJECTIVES: To report and explore potential reasons for undetectable or low-normal serum intact PTH levels in patients with surgically verified primary hyperparathyroidism with parathyroid adenomas, review the relevant literature, and offer suggestions for management of such patients occasionally encountered in clinical practice. For future research, to help understand mechanisms underlying 'undetectable' or inappropriately low serum intact PTH levels. METHODS: Serum intact PTH levels were measured pre- and postoperatively by immunochemiluminescent assay (ICMA) and the results were confirmed by at least two repeated measurements on different occasions in each patient. PATIENTS: We encountered two unusual patients with primary hyperparathyroidism who had suggestive biochemical and/or clinical features of primary hyperparathyroidism. However, serum intact PTH levels were either very low or undetectable in the context of hypercalcaemia, with no other obvious cause. A (99m)Tc sestamibi scan showed increased uptake in one of the parathyroid glands, suggesting a single adenoma in each case that was confirmed at surgery. RESULTS: In the first patient, from India, mean +/- SD serum calcium was 2.6 +/- 0.32 mmol/l (reference range 2.12-2.74 mmol/l) with intact PTH of 0.11 pmol/l (reference range 1.1-7.59 pmol/l). In the second patient, from the USA, mean +/- SD serum calcium and intact PTH were 2.9 +/- 0.07 mmol/l (reference range 2.17-2.51 mmol/l) and 1.35 pmol/l (reference range 1.1-7.59 pmol/l), respectively. Following curative parathyroidectomy, serum calcium levels normalized in both patients. By contrast, serum intact PTH levels, which were either suppressed or very low before surgery, rose into the low-normal reference range in all patients. CONCLUSIONS: When the clinical suspicion is high, the diagnosis of primary hyperparathyroidism should be pursued despite suppressed or low-normal serum intact PTH levels after carefully excluding other causes of hypercalcaemia. Further research on various intact PTH molecular species secreted by parathyroid adenomas or post-translational changes in the intact PTH molecule that might interfere with in vitro measurements should be undertaken to understand the precise reason(s) for such anomalous findings.

Measles virus nucleocapsid protein modulates the Signal Regulatory Protein-ß1 (SIRPß1) to enhance osteoclast differentiation in Paget's disease of bone.

Paget's disease of bone (PDB) is a chronic localized bone disorder in an elderly population. Environmental factors such as paramyxovirus are implicated in PDB and measles virus nucleocapsid protein (MVNP) has been shown to induce pagetic osteoclasts (OCLs). However, the molecular mechanisms underlying MVNP stimulation of OCL differentiation in the PDB are unclear. We therefore determined the MVNP regulated gene expression profiling during OCL differentiation. Agilent microarray analysis of gene expression identified high levels of SIRPß1 (353-fold) expression in MVNP transduced human bone marrow mononuclear cells stimulated with RANKL. Real-time PCR analysis further confirmed that MVNP alone upregulates SIRPß1 mRNA expression in these cells. Also, bone marrow mononuclear cells derived from patients with PDB showed high levels of SIRPß1 mRNA expression compared to normal subjects. We further show that MVNP increases SIRPß1 interaction with DAP12 adaptor protein in the presence and absence of RANKL stimulation. shRNA knockdown of SIRPß1 expression in normal human bone marrow monocytes decreased the levels of MVNP enhanced p-Syk and c-Fos expression. In addition, SIRPß1 knockdown significantly decreased MVNP stimulated dendritic cell-specific transmembrane protein (DC-STAMP) and connective tissue growth factor (CTGF) mRNA expression during OCL differentiation. Furthermore, we demonstrated the contribution of SIRPß1 in MVNP induced OCL formation and bone resorption. Thus, our results suggest that MVNP modulation of SIRPß1 provides new insights into the molecular mechanisms which control high bone turnover in PDB.

Protective effect of low-dose risedronate against osteocyte apoptosis and bone loss in ovariectomized rats.

Osteocyte apoptosis is the first reaction to estrogen depletion, thereby stimulating osteoclastic bone resorption resulting in bone loss. We investigated the effects of two different risedronate (RIS) doses (high and low) on osteocyte apoptosis, osteoclast activity and bone loss in ovariectomized rats. Forty rats with ovariectomy (OVX) and sham ovariectomy (SHAM) were divided into 4 groups: 1) SHAM rats treated with saline (SHAM); 2) OVX rats treated with saline (OVX); 3) OVX rats treated with low-dose RIS (OVX-LR, 0.08 µg/kg/day); 4) OVX rats treated with high-dose RIS (OVX-HR, 0.8 µg/kg/day). All animals were sacrificed 90 days after surgery for the examinations of osteocyte apoptosis by caspase-3 staining, osteoclast activity by TRAP staining and bone volume by micro-CT scanning in lumbar vertebral cancellous bone. Both low and high dose RIS significantly reduced caspase-3 positive osteocytes, empty lacunae and TRAP positive osteoclasts in OVX rats. Although the difference in caspase-3 positive osteocytes was not significant between the OVX-LR and OVX-HR groups, numerically these cells were significantly more prevalent in OVX-HR (not OVX-LR) group than in SHAM group. TRAP positive osteoclasts were significantly higher in OVX-LR group than in SHAM or OVX-HR group. There was no significant difference in bone volume among the OVX-LR, OVX-HR and SHAM groups, but lower in OVX group alone. However, significant increase in trabecular thickness only occurred in OVX-LR group. We conclude that both low and high dose RIS significantly inhibit osteocyte apoptosis and osteoclast activity in OVX rats, but the low-dose RIS has weaker effect on osteoclast activity. However, low-dose RIS preserves cancellous bone mass and microarchitecture as well as high-dose RIS after estrogen depletion.

Independent and combined contributions of cancellous and cortical bone deficits to vertebral fracture risk in postmenopausal women.

UNLABELLED: Using iliac bone histomorphometry on 78 patients with vertebral fracture and 66 healthy postmenopausal women, cortical thickness discriminated at least as well as any cancellous bone structural index between the two groups. Subjects with a deficit in both cortical and cancellous bone had much greater likelihood of fracture. INTRODUCTION: Vertebral fracture is often attributed to disproportional loss of cancellous bone, but fracture patients may have deficits in cortical and cancellous bone. Accordingly, we examined the contribution of cortical and cancellous bone deficits, separately and together, to the likelihood of vertebral fracture. MATERIALS AND METHODS: Iliac bone histomorphometry was performed in 78 white woman with clinically apparent vertebral fracture, 66 healthy postmenopausal women, and 38 healthy premenopausal women. We measured cancellous bone volume (Cn.BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th), cortical bone volume (Ct.BV/TV), and cortical thickness (Ct.Th). For each variable, a value of >1 SD below the mean in premenopausal women was treated as a putative risk factor, and its association with the presence or absence of fracture was determined by OR calculated by logistic regression and by receiver operating characteristic (ROC) curve analysis. Subsets of fracture and control subjects were separately matched for Cn.BV/TV and Ct.Th. RESULTS: All structural indices differed between fracture patients and controls except Ct.BV/TV. There was a weak but highly significant correlation between Cn.BV/TV and Ct.Th in the entire group (r = 0.389, r(2) = 0.151 p < 0.001). Many control subjects had a high value for one of these variables and a low value for the other. Ct.Th., Cn.BV/TV, and Tb.N were all significantly associated with vertebral fracture (ORs, 4.4-5.8; ROC area under the curve [AUC], 0.74-0.85). In subjects matched for Cn.BV/TV, Ct.Th was reduced by 29% (OR, 5.0), and in subjects matched for Ct.Th, Cn.BV/TV was reduced by 27% (OR, 5.0). In patients with deficits in both cortical and cancellous bone, the ORs ( 28-35 ) were much higher. CONCLUSIONS: Deficits in cortical bone (reduced value for Ct.Th) and in cancellous bone (reduced values for Cn.BV/TV or Tb.N) were equally effective in discriminating between subjects with and without vertebral fracture. With a deficit in both cortical and cancellous bone, the association with vertebral fracture was much stronger. Vertebral fracture is not the result of disproportionate loss of cancellous bone in the patients as a whole, although individual patients may have relatively greater deficits in either cancellous or cortical bone.

Differences in osteocyte and lacunar density between Black and White American women.

We examined the differences in osteocyte and lacunar density between Black and White women, using previously obtained iliac bone biopsies from 34 healthy Black women, aged 21-70 years, and 94 White women, aged 20-73 years. For each subject, the density of osteocytes (Ot.N/B.Ar), empty lacunae (EL.N/B.Ar), and total lacunae (Tt.L.N/B.Ar) and the proportion of osteocyte-occupied lacunae (Ot.N/Tt.L.N) were separately measured in whole trabeculae, superficial bone (<25 microm from the bone surface), and deep bone (>45 microm from the bone surface). Compared with White women, Black women had higher values for osteocytes, empty lacunae, and total lacunae and lower values for percent occupied lacunae in superficial bone and whole trabeculae (P < 0.01 to <0.001). In deep bone there were more osteocytes and total lacunae in Black women, but the other measurements did not differ significantly between the two groups. As in White women, there were fewer osteocytes and total lacunae and more empty lacunae in deep than in superficial bone. The regressions of osteocyte and total lacunar density on age were not significant in Black women, but postmenopausal Black women had fewer osteocytes than premenopausal Black women, and percent occupied lacunae declined significantly with age in whole trabeculae and deep bone, which could only have resulted from osteocyte death. In contrast to White women, there was no inverse relationship between bone formation rate and osteocyte density in superficial bone and the observed bone formation rate was lower than predicted by osteocyte density. We conclude the following: (1) Cancellous bone is made with more osteocytes in Black than in White women, most likely because of diminished apoptosis of osteoblasts; this could contribute to increased bone strength in Black women. (2) In Black women, as in White women, there are fewer osteocytes and total lacunae and more empty lacunae in deep than in superficial bone. (3) There was moderate age-related loss of osteocytes in deep bone in Black women, indicating that osteocyte density depends more on the age of the bone than on the age of the subject. (4) The higher osteocyte density in Black women was not responsible for their lower bone formation rate.

Effect of gastric bypass surgery on vitamin D nutritional status.

BACKGROUND: We previously reported a 60% prevalence of vitamin D (VitD) depletion, defined as a 25-hydroxyvitamin D (25-OHD) level of < or =20 ng/mL, in morbidly obese patients preoperatively. We now report the effect of gastric bypass (GB) on the VitD nutritional status in these patients. METHODS: We prospectively studied 108 morbidly obese patients who had undergone GB. Routine postoperative supplementation consisted of 800 IU VitD and 1500 mg calcium daily. Serum calcium, parathyroid hormone, and 25-OHD were measured before and 1 year after GB. RESULTS: The mean patient age was 46 +/- 9 years, 93% were women, and 72% were white. Preoperatively and at 1 year postoperatively, the prevalence of VitD depletion and hyperparathyroidism (HPT) and the mean 25-OHD level was 53% and 44%, 47% and 39%, and 20 and 24 ng/mL, respectively. One year after GB, the percentage of excess weight loss was 67% and demonstrated significant correlations both positively with 25-OHD and inversely with parathyroid hormone. At both intervals, blacks had a greater incidence of VitD depletion than did whites, and, at 1 year after GB, HPT was more common in patients with VitD depletion (55% versus 26%, P = .002). CONCLUSION: With customary supplementation, VitD nutrition is improved after GB, but VitD depletion persists in almost one half of patients, and blacks are at a significantly greater risk than whites. HPT did not improve, and those with VitD depletion had a significantly greater rate of HPT. Additional prospective studies are needed to determine how to optimize VitD nutrition and avoid potential long-term skeletal complications after GB.

Prevalence of vitamin D depletion among morbidly obese patients seeking gastric bypass surgery.

BACKGROUND: Abnormalities in calcium and vitamin D metabolism have been reported after bariatric surgery. The purpose of this study was to evaluate vitamin D nutritional status among morbidly obese patients before gastric bypass surgery. METHODS: We prospectively studied 279 morbidly obese patients seeking gastric bypass surgery for vitamin D nutritional status as assessed by serum 25-hydroxyvitamin D level. In addition, serum samples were analyzed for calcium, alkaline phosphatase (AP), intact parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D. RESULTS: Mean patient age was 43 +/- 9 years; 87% of the study patients were women, and 72% were white. Serum calcium and AP levels were normal in 88% and 89% of the patients, respectively. Vitamin D depletion, defined as serum 25-hydroxyvitamin D level

Severely suppressed bone turnover: a potential complication of alendronate therapy.

Alendronate, an inhibitor of bone resorption, is widely used in osteoporosis treatment. However, concerns have been raised about potential oversuppression of bone turnover during long-term use. We report on nine patients who sustained spontaneous nonspinal fractures while on alendronate therapy, six of whom displayed either delayed or absent fracture healing for 3 months to 2 yr during therapy. Histomorphometric analysis of the cancellous bone showed markedly suppressed bone formation, with reduced or absent osteoblastic surface in most patients. Osteoclastic surface was low or low-normal in eight patients, and eroded surface was decreased in four. Matrix synthesis was markedly diminished, with absence of double-tetracycline label and absent or reduced single-tetracycline label in all patients. The same trend was seen in the intracortical and endocortical surfaces. Our findings raise the possibility that severe suppression of bone turnover may develop during long-term alendronate therapy, resulting in increased susceptibility to, and delayed healing of, nonspinal fractures. Although coadministration of estrogen or glucocorticoids appears to be a predisposing factor, this apparent complication can also occur with monotherapy. Our observations emphasize the need for increased awareness and monitoring for the potential development of excessive suppression of bone turnover during long-term alendronate therapy.

The morphological association between microcracks and osteocyte lacunae in human cortical bone.

We studied the spatial relationship between the osteocyte lacunar-canalicular network and microdamage accumulation in bone matrix. Rib sections from 9 white women aged 50-60 were stained with basic fuchsin and examined using bright-field and fluorescence microscopy. The results showed that the numerical and length density of cracks were 5-fold higher in interstitial bone than in osteons (P<0.001). Osteocyte lacunar density was 17% lower in interstitial bone than in osteonal bone (P<0.001). In addition, the osteocyte lacunae in interstitial bone were significantly fewer (by 16%) in the area adjacent to microdamage as compared with the area remote from microdamage (P<0.001). The proportion of fields with lacunar density less than 728/mm2, the cut-off point calculated from ROC analysis, was 30% in osteonal bone, 55% in interstitial bone remote from microcracks and 83% adjacent to microcracks. The mean values of lacunar density in these bones were 10%, 22% and 27% lower than the cut-off point, respectively. The likelihood of microdamage was 3.8 times higher in bone with osteocyte lacunar density <728/mm2. About 73% of the crack profiles were spatially associated, at least partly, with bone fragments in which osteocyte lacunae were absent. We conclude that microdamage and osteocyte deficiency occur in the same bone regions; there is likely a causal relationship between them but we are unable to say which comes first.

Reduced iliac cancellous osteocyte density in patients with osteoporotic vertebral fracture.

UNLABELLED: Iliac cancellous osteocyte density declines with age, but its relationship to vertebral fracture pathogenesis is unknown. We performed iliac bone biopsy in 44 women with clinical vertebral fracture and 56 healthy women. The fracture patients had 34% fewer osteocytes but no reduction in percent occupied lacunae. Some patients destined to sustain vertebral fracture make cancellous bone with fewer osteocytes. INTRODUCTION: Patient's with vertebral fracture have less bone than appropriate healthy controls, but other factors may contribute to bone fragility. Iliac cancellous osteocyte density declines with age in healthy women; we asked whether this variable differed between fracture patients and healthy controls. METHODS: Two groups of women were assembled. Forty-four (mean age, 66.2 years) had unequivocal evidence of bone fragility manifested as painful nontraumatic vertebral fracture, and 56 (mean age, 62.2 years) were skeletally healthy. All subjects underwent iliac bone biopsy. From archival embedded biopsy cores, new sections were stained with Goldner's trichrome, in which we enumerated osteocyte-occupied lacunae (stained), empty lacunae (unstained), and total lacunae per bone area. RESULTS: Cancellous osteocyte density was 34% lower in the fracture group than in the controls (p < 0.001); this difference was not a consequence of higher turnover, having less bone, or the small difference in age. The area under the receiver operating characteristic (ROC) curve for discrimination between the groups was >90% for osteocyte density and <75% for bone volume/tissue volume (BV/TV). The disease-related osteocyte deficit was accompanied by a proportionate reduction in empty lacunae and no change in percent occupied lacunae; therefore, it was not the result of premature death. Both superficial bone (<25 microm from the surface) and deep bone (>45 microm from the surface) were affected. In contrast, the age-related deficit is accompanied by an increase in empty lacunae and fall in percent osteocyte-occupied lacunae and occurs only in deep bone, but not in superficial bone. CONCLUSIONS: In some patients destined to sustain spontaneous vertebral compression fracture, iliac cancellous bone is made with fewer osteocytes than normal; the mechanism of osteocyte incorporation into bone needs more detailed study. Osteocyte deficiency could contribute to bone fragility, either by impairing the detection of fatigue microdamage or by reducing canalicular fluid flow. Current practices of defining vertebral fracture based on morphometry alone regardless of symptoms, and diagnosing osteoporosis based on bone densitometry alone regardless of fracture history, should be reexamined.

Role of vitamin D and calcium nutrition in disease expression and parathyroid tumor growth in primary hyperparathyroidism: a global perspective.

Since the classic description by Fuller Albright in the 1940s, primary hyperparathyroidism has evolved from a disease with classic signs and symptoms to a disease in search of symptoms! Since that time, two major events have occurred. First, in the United States, United Kingdom, and in most European countries, there has been a steady rise in the apparent incidence of the disease. Second, there has been a dramatic shift in the pattern of presentation. A majority of patients with primary hyperparathyroidism in countries with multichannel screening panels are asymptomatic. Skeletal and renal complications are uncommon, and osteitis fibrosa is rare. In contrast, the clinical presentation of primary hyperparathyroidism has changed very little in other regions such as the East, the Middle East, and some parts of the southern hemisphere over the same period of observation. Accordingly, we assessed the influence of vitamin D and calcium nutrition on the disease expression and parathyroid tumor growth in patients with primary hyperparathyroidism from different parts of the world. Between 1945 and 1950, both the prevalence of osteitis fibrosa and parathyroid tumor weight declined dramatically in the United States, coinciding with fortification of milk with vitamin D. In contrast, osteitis fibrosa and parathyroid tumor weight changed very little in parts of the world where vitamin D depletion is endemic. Furthermore, for a comparable degree of vitamin D depletion, Asian Indians have significantly larger tumors compared with Americans (3.95 +/- 2.23 vs. 0.66 +/- 2.84 g; p < 0.001). Within the United States, blacks have larger tumors compared with whites (0.78 +/- 2.87 vs. 0.58 +/- 2.78 g; p < 0.01). However, the slopes of regression between serum 25-hydroxyvitamin D, the best index of vitamin D nutrition, and parathyroid tumor weight, the best available index of parathyroid growth, were not significantly different between Asian Indians, whites, and blacks. We conclude that vitamin D and calcium nutrition of the population affect both the clinical expression and parathyroid tumor growth in patients with primary hyperparathyroidism. It will be of interest to see if the pattern of presentation of primary hyperparathyroidism changes when better nutritional policies are implemented in developing countries.

Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism.

Parathyroidectomy is the definitive therapy for patients with symptomatic primary hyperparathyroidism. However, the role of surgery in mild asymptomatic primary hyperparathyroidism remains controversial. Accordingly, we conducted a prospective, randomized, controlled clinical trial of parathyroidectomy to determine the benefits of surgery vs. adverse effects of no surgery. Fifty-three patients were randomly assigned to either parathyroidectomy (n = 25) or regular follow-up (n = 28). Bone mineral density (BMD), biochemical indices of the disease, quality of life, and psychological function were measured at 6- or 12-month intervals for at least 24 months. Twenty-three of the 25 patients randomized to parathyroidectomy had surgery within the specified time of the protocol and three of the 28 patients randomized to regular follow-up had parathyroidectomy during follow-up. After parathyroidectomy, there was an increase in BMD of the spine (1.2%/yr, P < 0.001), femoral neck (0.4%/yr, P = 0.031), total hip (0.3%/yr, P = 0.07), and forearm (0.4%/yr, P < 0.001) and an expected fall in serum total and ionized calcium, serum PTH, and urine calcium (P < 0.001 for all). In contrast, patients followed up without surgery lost BMD at the femoral neck (-0.4%/yr, P = 0.117) and total hip (-0.6%/yr, P = 0.007) but gained at the spine (0.5%/yr; P = ns) and forearm (0.2%/yr, P = 0.047), with no significant changes in biochemical indices of disease. Consequently, a significant effect of parathyroidectomy on BMD was evident only at the femoral neck (a group difference of 0.8%/yr; P = 0.01) and total hip (a group difference of 1.0%/yr; P = 0.001) but not at the spine (a group difference of 0.6%/yr) or forearm (a group difference of 0.2%/yr). Quality-of-life scores as measured by a 36-item short-form health survey showed significant declines in five of the nine domains (social functioning, physical problem, emotional problem, energy, and health perception) in patients followed up without surgery but in only one of the nine domains (physical function) in the patients who had parathyroidectomy. Consequently, a modest measurable benefit of parathyroidectomy was evident in social and emotional role function (P = 0.007 and 0.012, respectively). Psychological function as assessed by the symptom checklist revised did not change significantly in either group, except for a significant decline in anxiety (P = 0.003) and phobia (P = 0.024) in patients who had surgery in comparison with those who did not. We conclude that it is feasible to conduct a randomized, controlled clinical trial of parathyroidectomy in patients with mild asymptomatic primary hyperparathyroidism, and measurable benefits of surgery on BMD, quality of life, and psychological function can be demonstrated. However, the small but significant benefits of parathyroidectomy must be weighed against the risks of surgery in these otherwise healthy individuals.