The prevalence and natural history of normocalcaemic hypoparathyroidism in a United Kingdom referral population.

CONTEXT: Normocalcaemic hypoparathyroidism (NHYPO) is characterized by low levels of parathyroid hormone (PTH) with normal levels of calcium. There is little in the current literature on this disease, with only two studies published on its prevalence, while its natural history remains relatively unknown. OBJECTIVES: To identify the prevalence of NHYPO in a UK referral population and to study the natural history of the disorder. DESIGN: Retrospective study. Five-year follow-up. PATIENTS: 6280 patients referred for a BMD measurement in a Metabolic Bone referral centre. MEASUREMENTS: Prevalence of NHYPO and variability of calcium. RESULTS: Based on laboratory results on the index day, 22 patients with NHYPO were identified. Four patients were excluded due to non-PTH-induced hypocalcaemia and unconfirmed data. The final prevalence was 0.29%. Only 67% had persistent normocalcaemia, and the rest had intermittent hypocalcaemia. Two of these patients also had persistently low PTH on two occasions. Most of the patients had one PTH measurement available. No patient developed permanent hypoparathyroidism. CONCLUSIONS: The prevalence calculated from this UK referral population is lower when compared to results from previous studies. NHYPO patients often have episodes of hypocalcaemia with some cases having no apparent reason for calcium levels below the reference range.

Normocalcemic Hyperparathyroidism: Study of its Prevalence and Natural History.

CONTEXT: Normocalcemic hyperparathyroidism (NPHPT) is characterized by persistently normal calcium levels and elevated parathyroid hormone (PTH) values, after excluding other causes of secondary hyperparathyroidism. The prevalence of the disease varies greatly and the data on the natural history of this disease are sparse and inconclusive. OBJECTIVES: The objectives of this study are to describe the prevalence of NPHPT and its natural history in a referral population and to compare the variability of serum calcium with a group of patients with primary hyperparathyroidism (PHPT). DESIGN: A retrospective study was conducted over 5 years. SETTING: The setting for this study was a metabolic bone referral center. PATIENTS: A total of 6280 patients were referred for a bone mineral density measurement (BMD). MAIN OUTCOME MEASURES: The prevalence and natural history of NPHPT and variability of calcium were the main outcome measures. RESULTS: We identified NPHPT patients using data from the day of the BMD measurement. We excluded patients with low estimated glomerular filtration rate (eGFR) or vitamin D, or with no measurements available. Based on the evaluation of their medical files, we identified 11 patients with NPHPT (prevalence 0.18%). Only 4 patients had consistent normocalcemia throughout their follow-up, with only 2 also having consistently high PTH. None had consistently normal eGFR or vitamin D.Intermittent hypercalcemia was present in 7 of the 11 NPHPT patients. The mean adjusted calcium was found to be significantly lower in the NPHPT group compared with the PHPT group but higher than the control group. PTH was similar for NPHPT and PHPT. These 2 groups had similar variability in serum calcium. CONCLUSIONS: NPHPT patients often have episodes of hypercalcemia. We believe that NPHPT is a mild form of PHPT.

Effect of Teriparatide Treatment on Circulating Periostin and Its Relationship to Regulators of Bone Formation and BMD in Postmenopausal Women With Osteoporosis.

Context: Treatment of postmenopausal osteoporosis with teriparatide parathyroid hormone amino terminal 1-34 increases bone formation and improves bone microarchitecture. A possible modulator of action is periostin. In vitro experiments have shown that periostin might regulate osteoblast differentiation and bone formation through Wnt signaling. The effect of teriparatide on periostin is not currently known. Objectives: To determine the effect of teriparatide treatment on circulating levels of periostin and other regulators of bone formation and investigate how changes in periostin relate to changes in bone turnover markers, regulators of bone formation, and bone mineral density (BMD). Participants and Design: Twenty women with osteoporosis; a 2-year open-label single-arm study. Intervention: Teriparatide 20 µg was administered by subcutaneous injection daily for 104 weeks. Periostin, sclerostin, and Dickkopf-related protein 1, procollagen type I N-terminal propeptide (PINP), and C-telopeptide of type I collagen were measured in fasting serum collected at baseline (two visits) and then at weeks 1, 2, 4, 12, 26, 52, 78, and 104. BMD was measured at the lumbar spine, total hip, and femoral neck using dual energy x-ray absorptiometry. Results: Periostin levels increased by 6.6% [95% confidence interval (CI), -0.4 to 13.5] after 26 weeks of teriparatide treatment and significantly by 12.5% (95% CI, 3.3 to 21.0; P < 0.01) after 52 weeks. The change in periostin correlated positively with the change in the lumbar spine BMD at week 52 (r = 0.567; 95% CI, 0.137 to 0.817; P < 0.05) and femoral neck BMD at week 104 (r = 0.682; 95% CI, 0.261 to 0.885; P < 0.01). Conclusions: Teriparatide therapy increases periostin secretion; it is unclear whether this increase mediates the effect of the drug on bone.

DIAGNOSIS OF ENDOCRINE DISEASE: Bone turnover markers: are they clinically useful?

Bone turnover markers (BTMs) are useful in clinical practice as they are inexpensive, and they have proven useful for treatment monitoring and identification of poor adherence. BTMs cannot be used in individual patients for identifying accelerated bone loss or an increase in fracture risk or in deciding on the optimal therapy. They are useful for monitoring both anti-resorptive and anabolic treatment. Response can be defined as a result that exceeds an absolute target, or by a change greater than the least significant change; if such a response is not present, then poor compliance or secondary osteoporosis are likely causes. A baseline BTM measurement is not always made; in that case, a value of BTM on anti-resorptive treatment that is low or low normal or above the reference interval for anabolic therapy may be taken to indicate a satisfactory response. We provide an approach to using these bone turnover markers in clinical practice by describing algorithms for anti-resorptive and anabolic therapy and describing the changes we observe in the clinical practice setting.

Performance of quantitative ultrasound measurements of bone for monitoring raloxifene therapy.

Raloxifene increases bone mineral density (BMD) and decreases vertebral fracture risk; the effects on quantitative ultrasound (QUS) variables, however, have been less well studied. We aimed to further evaluate the effectiveness of QUS for monitoring raloxifene treatment and withdrawal effects. Osteopenic, postmenopausal women (age=50-80 yr, n=125), who completed a 96-wk study (phase A) evaluating treatment compliance or monitoring, were invited to participate in a 96-wk raloxifene withdrawal study (phase B). Those originally receiving treatment were then randomized to continue on raloxifene (60 mg/d)+calcium (500 mg/d) (n=23) or to discontinue raloxifene and take placebo+calcium (500 mg/d) (n=23). Previously untreated women remained untreated (n=12). Yearly QUS and BMD measurements were performed. At the end of phase A, lumbar spine BMD (p=0.005), amplitude-dependent speed of sound (Ad-SoS) (p=0.006) and average SoS (p=0.040) decreased in untreated women but remained stable in treated women. Significant changes in Ad-SoS and ultrasonic bone profiler index had occurred in treated women by the end of phase B (p<0.01). All variables, except bone transmission time, were higher for those receiving any raloxifene treatment (p<0.05). Until further knowledge has been acquired, QUS measurement variables should only be used in conjunction with BMD when assessing changes in bone because of raloxifene therapy.

Depot medroxyprogesterone acetate use after peak bone mass is associated with increased bone turnover but no decrease in bone mineral density.

OBJECTIVE: To ascertain whether increased bone turnover in depot medroxyprogesterone acetate (DMPA) users after peak bone mass is associated with bone mineral loss. DESIGN: Three-year, observational, longitudinal study. SETTING: General practice and family planning clinics. PATIENT(S): Women over age 34: established DMPA users (n = 23), discontinuers (n = 14), and controls (n = 27). MAIN OUTCOME MEASURE(S): Change in spine and hip bone mineral density (BMD). RESULT(S): Despite increased biochemical markers of bone turnover in DMPA users, there was no decrease in BMD. Bone turnover markers did not correlate with change in BMD. CONCLUSION(S): In established DMPA users, after peak bone mass, a single normal BMD measurement could provide reassurance for long-term use. Measurement of bone turnover does not predict bone loss in DMPA users.

Effects of Depot medroxyprogesterone acetate on bone density and bone metabolism before and after peak bone mass: a case-control study.

INTRODUCTION: Depot medroxyprogesterone acetate (DMPA; Depo-Provera, Tadworth, UK) contraception is used by more than 9 million women worldwide and has a high usage among teenagers in the United Kingdom and the United States. Previous studies have found that DMPA use is associated with a bone density deficit. OBJECTIVES: This case-control matched study aims to eliminate potential confounding factors, identify whether the effect of DMPA on the skeleton is age specific, and determine the effects of DMPA on hormones and bone turnover. DESIGN/PARTICIPANTS: We measured bone density, bone turnover, and hormones in individually matched case-control pairs of women: 50 pairs aged 18-25 yr and 50 pairs aged 35-45 yr. RESULTS: DMPA use was associated with a 5% bone density deficit at the lumbar spine and hip in women who started DMPA use before age 20 yr but not after age 34 yr. Bone turnover was increased in DMPA users in both age groups. DMPA users had lower estradiol and higher IGF-I than controls, and younger DMPA users had higher dehydroepiandrosterone sulfate than controls. In a multiple regression model, estradiol and IGF-I were associated with bone turnover, but addition of DMPA to the model made the association with estradiol nonsignificant. CONCLUSIONS: DMPA use is associated with a bone density deficit at the spine and hip when used before peak bone mass. DMPA acts on the skeleton mainly through estrogen deficiency.

Comparison of densitometric and radiographic vertebral fracture assessment using the algorithm-based qualitative (ABQ) method in postmenopausal women at low and high risk of fracture.

UNLABELLED: Using ABQ diagnosis, the sensitivity to detect VF of densitometric versus radiographic assessment in 755 postmenopausal women was 71-81% and specificity was 97%. Misdiagnosis was influenced by image quality and was more common for mild deformities. INTRODUCTION: Using densitometric vertebral fracture assessment (VFA), prevalent fractures are identified when vertebral height appears reduced by >or=20%. However, this approach does not discriminate between osteoporotic vertebral fracture (VF) and nonosteoporotic deformity, which increases the false-positive rate. Algorithm-based qualitative diagnosis (ABQ) focuses on vertebral endplate fracture to exclude these deformities but has not been applied in VFA. We wished to determine whether densitometric image quality is adequate for ABQ assessment. Our aims were to (1) calculate agreement between VFA and radiography using ABQ to identify prevalent VF and (2) identify the primary reasons for any discordant diagnosis. METHODS: Radiographic and densitometric spine images for postmenopausal women at low risk (LR; n = 459) and high risk (HR; n = 298) of VF were assessed using ABQ. Agreement between imaging modalities for VF diagnosis was assessed by kappa statistics using ABQ radiographic readings as the gold standard. RESULTS: The prevalence of VF was 11-29% (radiography) and 9-26% (VFA) in the LR and HR groups, respectively. Agreement between imaging modalities was good or very good (kappa = 0.62-0.81 in the LR and HR populations). The sensitivity to detect women with VF by VFA was 71% and 84% in the LR and HR populations, respectively, and specificity was 97%. Fifty-two (77%) and 60 (61%) of vertebrae misclassified by VFA in the LR and HR populations were mild fractures and 37 (54%) and 62 (63%) were wedge fractures. One third of fractures missed by VFA were related to poor or unreadable image quality (n = 27 and 28 vertebrae in the LR and HR populations, respectively). CONCLUSIONS: There was good agreement between VFA and radiography using ABQ to identify prevalent VF in women at LR or HR of osteoporotic VF. Vertebrae misclassified by VFA were primarily mild fractures or deformities, and two thirds of all fractures missed by VFA were related to poor or unreadable image quality.

Risk factors for vertebral and nonvertebral fracture over 10 years: a population-based study in women.

UNLABELLED: Risk factors may vary for different types of fracture, in particular for vertebral fractures. We followed 367 women >50 yr of age from a population-based cohort for up to 10 yr. Factors that predicted vertebral rather than nonvertebral fractures related to physical weakness, poor health, and weight loss. Similar factors were also associated with greater bone loss at the hip. INTRODUCTION: Many risk factors predict fractures overall, but it is less clear whether certain factors relate to vertebral fractures in particular. The aim of this study was to compare the risk factors for vertebral and nonvertebral fractures. MATERIALS AND METHODS: We carried out a 10-yr prospective population-based study of 375 women who were 50-85 yr of age initially. At baseline, we measured BMD, blood and urine biochemistry, and anthropometric measurements. Medical and lifestyle data were obtained by questionnaire. Incident vertebral fractures were determined for 311 subjects from spinal radiographs at 0, 2, 5, 7, and 10 yr using an algorithm-based qualitative method, and nonvertebral fractures were confirmed radiographically. Relative risks were calculated by Cox regression analysis. RESULTS: During follow-up, 70 subjects sustained one or more nonvertebral fractures and 29 sustained one or more vertebral fractures. Risk factors that predicted both types of fracture included increasing age, decreasing BMD at all sites, prevalent vertebral fracture, and shorter estrogen exposure. For nonvertebral fractures only, the risk factors included low urinary creatinine and less frequent use of stairs. The factors for vertebral fractures included lighter weight, reduced body fat, heavy smoking, lower serum calcium, albumin, and thyroid T(3), weak grip strength, and poor physical capability. In a multivariate model, weight, fat mass, serum calcium and T(3), prevalent vertebral fracture, and physical capability remained significant. Furthermore, grip strength, serum albumin, weight loss, and physical capability were associated with rate of bone loss at the femoral neck, and a fast rate of bone loss was also associated with vertebral fractures. CONCLUSIONS: We conclude that overall frailty, which may consist of general poor health, small or thin body size, and lack of strength and physical capability, predicts vertebral fractures but is not a significant predictor of nonvertebral fractures. Bone loss rates are associated with similar risk factors and also with the incidence of vertebral fractures.

The discriminative ability of peripheral and axial bone measurements to identify proximal femoral, vertebral, distal forearm and proximal humeral fractures: a case control study.

Previous studies evaluating peripheral bone measurement devices have often used discontinued technologies, compared single devices, only evaluated a single fracture syndrome or failed to make a comparison with central densitometry, which is currently the gold standard for fracture discrimination. We have used a case control study to evaluate the ability of different peripheral and central bone techniques to discriminate between fracture cases and controls, determine the impact of different measurement sites, evaluate the role of measuring the cortical or trabecular envelopes using quantitative computed tomography (QCT) and determine the impact of using combinations of sites and techniques on fracture discrimination. We recruited postmenopausal women with proximal femoral (n=53), vertebral (n=73), distal forearm (n=78) or proximal humeral (n=75) fractures, and 500 population-based women (age 55-80 years). All subjects had measurements of the spine, total hip and distal forearm with dual-energy X-ray absorptiometry (DXA), distal forearm QCT and quantitative ultrasound (QUS) of the heel (four devices), finger (two devices), radius and metatarsal. The association of each device with fracture was expressed as the age-adjusted standardized odds ratios (sOR) per 1-SD decrease of population variance. The association of bone measurements with fracture was site-specific. We found the hip (sOR up to 3.40) and vertebral (sOR up to 4.67) fractures were more closely associated with central bone measurements than upper limb fractures (sOR 1.96 and 2.05). The performance of heel broadband ultrasound attenuation (sOR 2.09-2.41), heel speed of sound (sOR 1.79-2.28) and peripheral BMD (sOR 2.07 and 2.24) was comparable with total hip (sOR 2.46) and lumbar spine DXA (sOR 2.31) in discriminating all types of osteoporotic fracture. In general, measuring cortical or trabecular envelopes did not increase sOR. However, combining different measurement sites or technologies provided additional information, which was independent of total hip BMD. The ability of different bone measurements to discriminate between fracture cases and controls is device- and site-specific, with additional information obtained by combining measurement sites and technologies.

Effect of pamidronate on bone turnover and implant migration after total hip arthroplasty: a randomized trial.

In this trial we studied the effect of pamidronate on periprosthetic bone turnover and pelvic implant migration over 2 years after hybrid total hip arthroplasty (THA). Twenty-two patients received 90 mg of pamidronate and 22 received placebo at randomization 5 days after surgery. Rapid periprosthetic bone loss occurred in the placebo group over the first 6 months and was accompanied by transient increases in biochemical markers of bone turnover. Partial recovery in bone mass occurred in most regions after this period. No recovery of bone mass occurred at the femoral calcar or the medial wall of the acetabulum. Femoral calcar bone loss at 2 years was strongly predicted by acute biomarker changes at week 6. Pamidronate therapy reduced femoral bone loss in the region of the femoral calcar (P = 0.01), but did not affect pelvic bone loss. Pamidronate therapy also inhibited the transient rise in biochemical markers of bone turnover during this period. Pamidronate therapy did not affect acetabular cup migration. Cup migration was inversely related to subject age, but unrelated to initial post-operative bone mineral density, or subsequent bone loss. In summary, early periprosthetic bone loss is associated with a transient expansion of the bone remodeling space. Bisphosphonate therapy reduces femoral calcar bone loss and bone turnover after THA, but did not influence cup migration in this study. Acute changes in biochemical markers predict femoral periprosthetic bone loss.

The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial.

Long-term adherence and persistence with any therapy are very poor ( approximately 50%). Adherence to therapy is defined as the percentage of prescribed medication taken, and persistence is defined as continuing to take prescribed medication. We examined whether monitoring by nursing staff could enhance adherence and persistence with antiresorptive therapy and whether presenting information on response to therapy provided additional benefit. In addition we evaluated the impact of monitoring on treatment efficacy. Seventy-five postmenopausal women with osteopenia were randomized to 1) no monitoring, 2) nurse-monitoring, or 3) marker-monitoring. All subjects were prescribed raloxifene. At 12, 24, and 36 wk, the nursing staff reviewed subjects in the monitored (nurse-monitoring or marker-monitoring) groups using a predefined protocol. The marker-monitored group were also presented a graph of response to therapy using percentage change in urinary N-telopeptide of type I collagen (uNTX), a bone resorption marker, at each visit. Biological response to therapy at 1 yr was determined using the percent change in bone mineral density (BMD) and uNTX. Treatment adherence and persistence were assessed using electronic monitoring devices. Survival analysis showed that the monitored group increased cumulative adherence to therapy by 57% compared with no monitoring (P = 0.04). There was a trend for the monitored group to persist with therapy for 25% longer compared with no monitoring (P = 0.07). Marker measurements did not improve adherence or persistence to therapy compared with nurse-monitoring alone. Adherence at 1 yr was correlated with percent change in hip (BMD) (r = 0.28; P = 0.01) and percent change in uNTX (r = -0.36; P = 0.002). In conclusion, monitoring of patients increased adherence to therapy by 57% at 1 yr. Increased adherence to therapy increased the effectiveness of raloxifene therapy determined using surrogate end points.