Mutations in Known Monogenic High Bone Mass Loci Only Explain a Small Proportion of High Bone Mass Cases.

High bone mass (HBM) can be an incidental clinical finding; however, monogenic HBM disorders (eg, LRP5 or SOST mutations) are rare. We aimed to determine to what extent HBM is explained by mutations in known HBM genes. A total of 258 unrelated HBM cases were identified from a review of 335,115 DXA scans from 13 UK centers. Cases were assessed clinically and underwent sequencing of known anabolic HBM loci: LRP5 (exons 2, 3, 4), LRP4 (exons 25, 26), SOST (exons 1, 2, and the van Buchem's disease [VBD] 52-kb intronic deletion 3'). Family members were assessed for HBM segregation with identified variants. Three-dimensional protein models were constructed for identified variants. Two novel missense LRP5 HBM mutations ([c.518C>T; p.Thr173Met], [c.796C>T; p.Arg266Cys]) were identified, plus three previously reported missense LRP5 mutations ([c.593A>G; p.Asn198Ser], [c.724G>A; p.Ala242Thr], [c.266A>G; p.Gln89Arg]), associated with HBM in 11 adults from seven families. Individuals with LRP5 HBM (∼prevalence 5/100,000) displayed a variable phenotype of skeletal dysplasia with increased trabecular BMD and cortical thickness on HRpQCT, and gynoid fat mass accumulation on DXA, compared with both non-LRP5 HBM and controls. One mostly asymptomatic woman carried a novel heterozygous nonsense SOST mutation (c.530C>A; p.Ser177X) predicted to prematurely truncate sclerostin. Protein modeling suggests the severity of the LRP5-HBM phenotype corresponds to the degree of protein disruption and the consequent effect on SOST-LRP5 binding. We predict p.Asn198Ser and p.Ala242Thr directly disrupt SOST binding; both correspond to severe HBM phenotypes (BMD Z-scores +3.1 to +12.2, inability to float). Less disruptive structural alterations predicted from p.Arg266Cys, p.Thr173Met, and p.Gln89Arg were associated with less severe phenotypes (Z-scores +2.4 to +6.2, ability to float). In conclusion, although mutations in known HBM loci may be asymptomatic, they only account for a very small proportion (∼3%) of HBM individuals, suggesting the great majority are explained by either unknown monogenic causes or polygenic inheritance.

Is Etanercept 25 mg Once Weekly as Effective as 50 mg at Maintaining Response in Patients with Ankylosing Spondylitis? A Randomized Control Trial.

OBJECTIVE: To investigate, in a pilot randomized controlled trial, whether etanercept (ETN) 25 mg once weekly is effective at maintaining a clinical response in patients with ankylosing spondylitis (AS) who have responded to the standard 50 mg dose. METHODS: Adults with AS not responding to conventional therapies were prescribed ETN 50 mg once weekly for 6 months. Responders as defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were randomly assigned to taper to 25 mg once weekly or continue on 50 mg and followed for a further 6 months. The primary outcome measure was maintenance of a 50% reduction in the BASDAI or fall in BASDAI by ≥ 2 units and a ≥ 2-unit reduction in BASDAI spinal pain as measured on a 10-point visual analog scale at 6 months postrandomization. RESULTS: Of 89 patients assessed for eligibility, 59 were enrolled; 47 (80%) had sufficient clinical response and were eligible for randomization, 24 were assigned to continue receiving ETN 50 mg, and 23 to taper to 25 mg. After 6 months, 20 (83%) of the 50 mg arm maintained clinical response compared with 12 (52%) of the 25 mg arm (a difference of -31%, 95% CI -58% - -5%). CONCLUSION: Although this pilot study demonstrates that treatment with ETN 25 mg was less effective at maintaining treatment response in the stepdown phase, 52% of participants maintained treatment response. Future research should address which patients are suitable for tapering.

Effects of growth hormone replacement on parathyroid hormone sensitivity and bone mineral metabolism.

Adult GH deficiency (AGHD) is associated with reduced bone mineral density, and decreased end-organ sensitivity to the effects of PTH has been suggested as a possible underlying mechanism. We investigated the effects of GH replacement (GHR) on PTH circulating activity and its association with phosphocalcium metabolism and bone turnover in 16 (8 men and 8 women) AGHD patients. Half-hourly blood and 3 hourly urine sampling was performed on each patient over a 24-h period before GHR and then after 1, 3, 6, and 12 months of GHR. GH was commenced at a dose of 0.5 IU/d and was titrated to achieve and maintain an IGF-I SD score within 2 SD of the age-related reference range. The target IGF-I SD score was achieved within 3 months and was maintained at 12 months after GHR in all patients. Our results demonstrated a significant decrease in serum PTH at all visits after GHR compared with baseline values (P < 0.001), with a concomitant increase in nephrogenous cAMP excretion at 1 (P < 0.001) and 3 (P < 0.05) months and increases in serum calcium (P < 0.001), serum phosphate (P < 0.001), 1,25-dihydroxyvitamin D(3) (P < 0.001), type I collagen C-telopeptide (a bone resorption marker; P < 0.001), and procollagen type I amino-terminal propeptide (a bone formation marker; P < 0.001). Simultaneously, we observed a significant decrease in urinary calcium excretion (P < 0.001) and an increase in maximum tubular phosphate reabsorption (P < 0.001). Together these results suggest increased end-organ responsiveness to the effects of circulating PTH resulting in increased bone turnover and reduced calcium excretion. Significant circadian rhythms were observed for serum PTH, phosphate, type I collagen C-telopeptide, and procollagen type I amino-terminal propeptide before and after GHR. However, sustained PTH secretion was observed between 1400-2200 h, with a reduced nocturnal rise in untreated AGHD patients, whereas PTH secretion decreased significantly between 1400-2200 h (P < 0.001), with a significant increase in nocturnal PTH secretion (P < 0.001) after 12 months of GHR. Our results demonstrate that GH may have a regulatory role in bone mineral metabolism, and our data provide a possible underlying mechanism for the development of osteoporosis in AGHD patients. The changes observed after GHR may further explain the beneficial effects of GHR on bone mineral density that have consistently been reported.

HIV infection--a risk factor for osteoporosis.

Osteopenia and osteoporosis have recently been described as complications of antiretroviral therapy in HIV-infected patients. The advent of highly active antiretroviral therapy in conjunction with improved standard antiviral and antibiotic regimens has dramatically changed the clinical course of HIV infection, resulting in prolonged survival. The pathogenesis and role of each individual medication are poorly understood. Avascular necrosis has also been described in AIDS patients receiving or not receiving antiretroviral therapy. This article is a clinically focused review of the literature on osteopenia, osteoporosis, and mineral metabolism related to HIV infection. In patients with HIV infection, the risks of osteopenia and osteoporosis are not very clear. The suggested risk factors for the development of osteopenia are use of protease inhibitors, longer duration of HIV infection, high viral load, high lactate levels, low bicarbonate levels, raised alkaline phosphatase level, and lower body weight before antiretroviral therapy. There have also been a few case reports of pathologic fractures in AIDS patients with antiretroviral therapy-induced osteopenia and osteoporosis. The underlying mechanism triggering bone loss in HIV-infected patients is unknown. The proinflammatory cytokines tumor necrosis factor and interleukin-6 have been found to be constitutionally produced in increased amounts in HIV-positive individuals, and they may have a role in osteoclast activation and resorption. Serum markers of bone formation are decreased and resorption is increased in patients with advanced clinical disease. Hypocalcemia, hypercalcemia, and abnormalities of the parathyroid hormone axis have been described in HIV infection. Histomorphometric analyses have shown altered bone remodeling in HIV-infected patients when compared with controls. Patients with known risk factors for osteoporosis-advancing age, low body weight, and prolonged duration of HIV infection-and those receiving protease inhibitor treatment should be considered for dual x-ray absorptiometry imaging. If bone mineral density is osteopenic or osteoporotic, then the patient should also be screened for other known medical causes of osteoporosis and consider treatment with a bisphosphonate or, if hypogonadal, testosterone replacement under close monitoring.

Parathyroid responsiveness to hypocalcemic and hypercalcemic stimuli in adult growth hormone deficiency after growth hormone replacement.

Adult growth hormone deficiency (AGHD) is associated with osteoporosis. Previous reports have suggested that alterations in parathyroid gland responsiveness to changes in calcium concentration may play a role in the genesis of osteoporosis in untreated AGHD patients. We investigated the endogenous parathyroid hormone [PTH-(1-84)] response to hypocalcemic and hypercalcemic stimuli induced by sodium EDTA and calcium gluconate infusion, respectively, and to PTH-(1-34) infusion in AGHD patients before and during GH replacement (GHR). We have demonstrated that the maximum PTH-(1-84) stimulation and suppression occurred at significantly higher calcium concentrations and in response to smaller changes in calcium concentrations after GHR. The calcemic response to the effects of PTH-(1-34) infusion significantly increased after GHR. The calcium set point (the calcium concentration at which the rate of PTH secretion is one-half of its maximal value) significantly increased in all groups after 3 mo on GHR, and it increased further at 12 mo. Our results suggest increased parathyroid gland sensitivity to smaller changes in serum calcium and increased end-organ sensitivity to the effects of PTH in AGHD patients after GHR. These findings may help us to understand the mechanisms underlying the genesis of osteoporosis in AGHD patients.