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Sclerostin is a 190 amino acid protein secreted primarily by osteocytes. It was initially identified due to mutations in the SOST gene associated with high bone mass phenotypes. Much recent work has sought to determine the importance of sclerostin across an array of conditions which affect the human skeleton. However, accurate measurement of sclerostin from serum and plasma sources remains a significant impediment, with currently available commercial assays showing marked differences in measured sclerostin values. Accordingly, sclerostin assay standardization remains an important but unmet need before sclerostin measurements can be used for the clinical management of bone disease. Here we characterize a novel automated chemiluminescent sclerostin assay (LIAISON(®), DiaSorin) which overcomes many of these limitations. Important assay characteristics include: a wide dynamic range (50–6500 pg/mL); high intra- (

Denosumab is a fully human monoclonal antibody against receptor activator of NF-κB ligand (RANKL) that decreases osteoclast formation, function and survival, and is approved for the treatment of postmenopausal women with osteoporosis at increased or high risk for fracture, among other indications. During the pivotal 3-year fracture trial FREEDOM, denosumab 60 mg subcutaneously every 6 months significantly reduced new vertebral (68%), hip (40%), and nonvertebral (20%) fractures; increased bone mineral density (BMD); and reduced bone turnover markers compared with placebo in postmenopausal women with osteoporosis. Questions have arisen regarding imbalances of certain low-frequency adverse events (AEs) observed in FREEDOM, as well as the top 5 most frequent adverse reactions listed in the United States prescribing information (USPI; back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis). We examined the incidences of these AEs in women who originally received placebo during FREEDOM and then received denosumab for up to 3 years during the FREEDOM Extension (Crossover Group). This provided a unique opportunity for comparison with the original 3-year denosumab FREEDOM observations. We also examined the incidences of these AEs over 6 years of denosumab treatment (Long-term Group; ie, comparing a second 3 years of treatment with findings in the first 3 years). There was no indication of increasing trends regarding the imbalances of either low-frequency AEs or common AEs observed in FREEDOM. © 2017 American Society for Bone and Mineral Research.

Effects on bone material properties of two-year antiosteoporotic treatment were assessed using in vivo impact microindentation (IMI) in patients with low bone mineral density (BMD) values. Antiresorptive treatment, in contrast to vitamin D +/- calcium treatment alone, induced BMD-independent increases in bone material strength index, measured by IMI, the magnitude of which depended on pretreatment values.Introduction Bone material strength index (BMSi), measured by IMI in vivo, is reduced in patients with fragility fractures, but there is no information about changes in values during long-term therapy. In the present study, we assessed changes in BMSi in patients receiving antiosteoporotic treatments for periods longer than 12 months.Methods We included treatment-naive patients with low bone mass who had a BMSi measurement with OsteoProbe (R) at presentation and consented to a repeat measurement after treatment. Results We studied 54 patients (34 women), median age 58 years, of whom 30 were treated with bisphosphonates or denosumab (treatment group) and 24 with vitamin D +/- calcium alone (control group). There were no differences in clinical characteristics between the two groups with the exception of a higher number of previous fragility fractures in the treatment group. Baseline hip BMD and BMSi values were lower in the treatment group. After 23.1 +/- 6.6 months, BMSi increased significantly in the treatment group (82.4 +/- 4.3 vs 79.3 +/- 4.1;p < 0.001), but did not change in the control group (81.5 +/- 5.2 vs 82.2 +/- 4.1;p = 0.35). Changes in BMSi with antiresorptives were inversely related with baseline values (r = - 0.43;p = 0.02) but not with changes in BMD. Two patients in the control group with large decreases in BMSi values sustained incident fractures.Conclusion In patients at increased fracture risk, antiresorptive treatments induced BMD-independent increases in BMSi values, the magnitude of which depended on pretreatment values.

Context Antiresorptive therapy has been associated with osteonecrosis of the jaw (ONJ), an infrequent but potentially serious adverse event. Objective To assess information on invasive oral procedures and events (OPEs)-dental implants, tooth extraction, natural tooth loss, scaling/root planing, and jaw surgery-during the 7-year Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Extension study and to present details of positively adjudicated ONJ cases. Design Randomized, double-blind, placebo-controlled, 3-year trial (FREEDOM) followed by 7 years of open-label denosumab (FREEDOM Extension). At Extension Year 3, women were asked to record their history of invasive OPEs since the start of the Extension to Year 2.5 and oral events in the prior 6 months. The questionnaire was then administered every 6 months until the end of the Extension. Setting Multicenter, multinational clinical trial. Patients Postmenopausal women with osteoporosis. Interventions Subcutaneous denosumab 60 mg or placebo every 6 months for 3 years, then 7 years of open-label denosumab. Main outcome measures Self-reports of OPEs and adjudicated cases of ONJ. Results Of respondents, 45.1% reported at least one invasive OPE. The exposure-adjusted ONJ rate in FREEDOM Extension was 5.2 per 10,000 person-years. ONJ incidence was higher in those reporting an OPE (0.68%) than not (0.05%). Conclusions Although invasive OPEs were common in these denosumab-treated women and were associated with an increased ONJ incidence, the overall rate of ONJ was low, and all cases with complete follow-up resolved with treatment.

Purpose In women with postmenopausal osteoporosis, we investigated the effects of 24 months of treatment with alendronate (ALN) following 18 months of treatment with abaloparatide (ABL) or placebo (PBO). Methods Women who completed ABL or PBO treatment in ACTIVE were eligible to receive up to 24 months of ALN. We evaluated the incidence of vertebral and nonvertebral fractures and changes in bone mineral density (BMD) during the entire 43-month period from ACTIVE baseline to the end of ACTIVExtend and for the 24-month extension only. Results Five hundred fifty-eight women from ACTIVE’s ABL group and 581 from its PBO group (92% of ABL and PBO completers) were enrolled. During the full 43-month treatment period, 0.9% of evaluable women in the ABL/ALN group experienced a new radiographic vertebral fracture vs 5.6% of women in the PBO/ALN group, an 84% relative risk reduction (RRR, P < 0.001). Kaplan–Meier incidence rates for other reported fracture types were significantly lower for ABL/ALN vs PBO/ALN (all P < 0.05). Gains in BMD achieved during ACTIVE were further increased during ACTIVExtend. For ACTIVExtend only, RRR for vertebral fractures was 87% with ABL/ALN vs PBO/ALN (P = 0.001). Adverse events were similar between groups. A supplemental analysis for regulatory authorities found no hip fractures in the ABL/ALN group vs five in the PBO/ALN group. Conclusions Eighteen months of ABL followed by 24 months of ALN reduced the risk of vertebral, nonvertebral, clinical, and major osteoporotic fractures and increased BMD. Sequential ABL followed by ALN appears to be an effective treatment option for postmenopausal women at risk for osteoporosis-related fractures., In ACTIVExtend, reductions in fracture risk and increases in BMD achieved with 18 months of abaloparatide for postmenopausal osteoporosis were sustained through 24 months of subsequent alendronate.

Summary This post-hoc analysis queried whether women experiencing fracture on denosumab indicates inadequate treatment response or whether the risk of subsequent fracture remains low with continuing denosumab. Results showed that denosumab decreases the risk of subsequent fracture and fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response. Introduction This analysis assessed whether a fracture sustained during denosumab therapy indicates inadequate treatment response and if the risk of a subsequent fracture decreases with continuing denosumab treatment. Methods In FREEDOM, a clinical trial to evaluate the efficacy and safety of denosumab, postmenopausal women with osteoporosis were randomized to placebo or denosumab for 3 years. In the 7-year FREEDOM Extension, all participants were allocated to receive denosumab. Here we compare subsequent osteoporotic fracture rates between denosumab-treated subjects during FREEDOM or the Extension and placebo-treated subjects in FREEDOM. Results During FREEDOM, 438 placebo- and 272 denosumab-treated subjects had an osteoporotic fracture. Exposure-adjusted subject incidence per 100 subject-years was lower for denosumab (6.7) vs placebo (10.1). Combining all subjects on denosumab from FREEDOM and the Extension for up to 10 years (combined denosumab), 794 (13.7%) had an osteoporotic fracture while on denosumab. Of these, one or more subsequent fractures occurred in 144 (18.1%) subjects, with an exposure-adjusted incidence of 5.8 per 100 subject-years, similar to FREEDOM denosumab (6.7 per 100 subject-years) and lower than FREEDOM placebo (10.1 per 100 subject-years). Adjusting for prior fracture, the risk of having a subsequent on-study osteoporotic fracture was lower in the combined denosumab group vs placebo (hazard ratio [95% CI]: 0.59 [0.43–0.81]; P = 0.0012). Conclusions These data demonstrate that denosumab decreases the risk of subsequent fracture and a fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response. Electronic supplementary material The online version of this article (10.1007/s00198-018-4687-2) contains supplementary material, which is available to authorized users.

Summary Background Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis. Methods In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60–90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov. Findings Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius. Interpretation Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. Funding Amgen.

Background Denosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study. Methods To understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study. Results Extension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (–1.9 and –2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX®) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively). Conclusion The observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects. Trial registration ClincalTrials.gov registration number NCT00523341; registered August 30, 2007 Electronic supplementary material The online version of this article (doi:10.1186/s12891-017-1520-6) contains supplementary material, which is available to authorized users.

Summary The FREEDOM study and its Extension provide long-term information about the effects of denosumab for the treatment of postmenopausal osteoporosis. Treatment for up to 8 years was associated with persistent reduction of bone turnover, continued increases in bone mineral density, low fracture incidence, and a favorable benefit/risk profile. Introduction This study aims to report the results through year 5 of the FREEDOM Extension study, representing up to 8 years of continued denosumab treatment in postmenopausal women with osteoporosis. Methods Women who completed the 3-year FREEDOM study were eligible to enter the 7-year open-label FREEDOM Extension in which all participants are scheduled to receive denosumab, since placebo assignment was discontinued for ethical reasons. A total of 4550 women enrolled in the Extension (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively. Results Throughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed in both groups. In the long-term group, mean bone mineral density (BMD) continued to increase significantly at each time point measured, for cumulative 8-year gains of 18.4 and 8.3 % at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased significantly from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2 % at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low in both groups. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed. Conclusions Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile. Electronic supplementary material The online version of this article (doi:10.1007/s00198-015-3234-7) contains supplementary material, which is available to authorized users.

This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes. Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients. IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis. This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity. This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.

Summary Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. Introduction Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. Methods The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score ≤−2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score ≤−1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. Results Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. Conclusions This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants. Electronic supplementary material The online version of this article (doi:10.1007/s00198-014-2944-6) contains supplementary material, which is available to authorized users.

Summary: Despite the proven predictive ability of bone mineral density, Fracture Risk Assessment Tool ( FRAX® ), bone turnover markers, and fracture for osteoporotic fracture, their use as targets for treatment of osteoporosis is limited. Introduction: Treat-to-target is a strategy applied in several fields of medicine and has recently become an area of interest in the management of osteoporosis. Its role in this setting remains controversial. This article was prepared following a European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis ( ESCEO ) working group meeting convened under the auspices of the International Osteoporosis Foundation ( IOF ) to discuss the feasibility of applying such a strategy in osteoporosis in Europe. Methods: Potential targets range from the absence of an incident fracture to fixed levels of bone mineral density ( BMD ), a desired FRAX® score, a specified level of bone turnover markers or indeed changes in any one or a combination of these parameters. Results: Despite the proven predictive ability of all of these variables for fracture ( particularly BMD and FRAX ), their use as targets remains limited due to low sensitivity, the influence of confounders and current lack of evidence that targets can be consistently reached. Conclusion: ESCEO considers that it is not currently feasible to apply a treat-to-target strategy in osteoporosis, though it did identify a need to continue to improve the targeting of treatment to those at higher risk ( target-to-treat strategy ) and a number of issues for the research agenda. These include international consensus on intervention thresholds and definition of treatment failure, further exploration of the relationship between fracture and BMD, and FRAX and treatment efficacy and investigation of the potential of short-term targets to improve adherence.

The role of proton transport and production in osteoclast differentiation was studied in vitro by inhibiting the transcription/translation of carbonic anhydrase II (CA II) and vacuolar H(+)-ATPase (V-ATPase) by antisense RNA molecules. Antisense RNAs targeted against CA II, or the 16 kDa or 60 kDa subunit of V-ATPase were used to block the expression of the specific proteins. A significant decrease in bone resorption rate and TRAP-positive osteoclast number was seen in rat bone marrow cultures and fetal mouse metacarpal cultures after antisense treatment. Intravacuolar acidification in rat bone marrow cells was also significantly decreased after antisense treatment. The CA II antisense RNA increased the number of TRAP-positive mononuclear cells, suggesting inhibition of osteoclast precursor fusion. Antisense molecules decreased the number of monocytes and macrophages, but increased the number of granulocytes in marrow cultures. GM-CSF, IL-3 and IL-6 were used to stimulate haematopoietic stem cell differentiation. The 16 kDa V-ATPase antisense RNA abolished the stimulatory effect of GM-CSF, IL-3 and IL-6 on TRAP-positive osteoclast formation, but did not affect the formation of monocytes and macrophages after IL-3 treatment, or the formation of granulocytes after IL-6 treatment. These results suggest that CA II and V-ATPase are needed, not only for the actual resorption, but also for osteoclast formation in vitro.

The authors, all physicians involved in clinical research on bone and practicing clinicians, propose practical guidelines for identifying persons with osteoporosis or those at high risk of developing the disease and for managing patients who may benefit from therapy. These guidelines are based on an analysis of peer-reviewed articles published before November 1998. A flowchart of women who might benefit from treatment is provided, including clinical presentation (recent fracture of the spine, hip, or other bone or no fracture; risk factors for osteoporosis); relevant investigations (bone mineral density measurement and laboratory tests required for the differential diagnosis); and therapeutic management (general measures such as calcium and vitamin D supplementation and specific pharmacologic interventions such as estrogen, bisphosphonates, intranasal calcitonin, raloxifene, fluoride salts, and other compounds that have been assessed in randomized clinical trials). The strongest evidence for antifracture efficacy (reduction of vertebral and nonvertebral fracture risk) was observed with alendronate.

Evidence is mounting that changes in the ability of cancer cells to adhere to extracellular matrices play a decisive role in metastatic spread. The mechanism underlying the preference of breast cancer cells to metastasize to bone is, however, poorly understood. We investigated the expression and involvement of integrin adhesion receptors in the adhesion of breast cancer cells to bone matrix (constituents) in two in vitro attachment assays using RGD peptides and anti-integrin antibodies. Breast cancer cells adhered rapidly to extracellular bone matrix. Adhesion of most cells to vitronectin, fibronectin, thrombospondin, osteopontin, and the fairly bone-specific bone sialoprotein was inhibited by the 200 micrograms/ml GRGDS peptide. These data suggest that integrin adhesion receptors can modulate the attachment of breast cancer cells to bone matrix molecules. In accordance with these findings, we found that alpha 1-alpha 5(beta 1) and alpha v(beta 3) integrins were expressed by mammary carcinoma cells. Highly tumorigenic MDA-MB-231 cells, which form osteolytic metastases in vivo, expressed relatively high levels of alpha 2 beta 1, alpha 3 beta 1, alpha 5 beta 1, alpha v beta 3 integrins, when compared to MCF-7, T47D, and ZR75-1 breast cancer cells. Addition of function-blocking anti-alpha 2 beta 1, -alpha 3 beta 1, -alpha 5 beta 1, and -alpha v beta 3 antibodies significantly inhibited the adhesion of MDA-MB-231 breast cancer cells to bone matrices. In conclusion, our data suggest a possible role for beta 1 and beta 3 integrin subfamily members in the establishment of skeletal metastases in advanced breast cancer patients. Clearly, functional evidence is required to understand the mechanisms involved in the development of skeletal metastases in breast cancer patients.

The primary aim of any intervention in osteoporosis is the prevention of fractures in individuals who have not yet fractured or the prevention of the progression of the disease in individuals with fragility fractures. There is currently insufficient evidence to recommend either a population-based prevention strategy or a strategy based on general screening with treatment of those individuals identified at high risk. Identification of subjects with strong clinical risk factors for osteoporotic fractures with subsequent measurement or not of bone mineral density as well as those with fragility fractures constitute at present the most rational approach to fracture prevention. Current measures to prevent osteoporotic fractures aim mainly at influencing bone mass and bone turnover and reducing the risk and impact of falls. Interventions that can reduce effectively the frequency of osteoporotic fractures in subjects at risk are available and new or alternative interventions are being developed. Issues related to the impact of these interventions on public health and health economics need to be addressed and methods to calculate the clinical outcomes in a way allowing comparison with outcomes of interventions in other common diseases should be developed.

Prednisone is frequently used in the treatment of elderly-onset rheumatoid arthritis (RA), but the balance between efficacy and toxicity, including the effect on bone mass, has not been investigated in long-term studies. This prospective, randomized study was undertaken to compare disease activity and bone mass during long-term treatment with prednisone versus chloroquine in this patient population.Patients with active RA diagnosed at ageor = 60 were randomized to receive prednisone (15 mg/day for 1 month, with the dosage tapered as low as possible thereafter) (n = 28) or chloroquine (n = 28). Patients who did not show a response received other second-line drugs as an adjunct to prednisone or as a replacement for chloroquine. Bone mass was measured by dual-energy x-ray absorptiometry. The study duration was 2 years.During the 2 years, treatment with other second-line drugs was needed for 12 patients in the prednisone group (43%) and 8 in the chloroquine group (29%). Functional capacity and disease activity improved significantly in both groups and did not differ significantly between the groups, except for a greater improvement in the prednisone group at 1 month. Radiographic scores for joint destruction progressed similarly in both groups. There was a nonsignificant excess bone loss of 1.8% in the spine and 1.5% in the hip in the prednisone group, compared with the chloroquine group.Neither treatment was entirely satisfactory since a significant number of patients needed an additional second-line drug over the 2-year period.

Humoral hypercalcemia of malignancy is a paraneoplastic syndrome believed to be due to production by the tumor of substances that stimulate osteoclastic bone resorption primarily. The human renal cell carcinoma cell line RC-8, grown in nude mice, was investigated for factors involved in renal cancer-induced hypercalcemia. At a tumor load of 200 to 400 mm.3 the mice developed hypercalcemia and hypophosphatemia associated with a rise in serum 1,25-dihydroxyvitamin D concentration and cachexia. The tumor released 1) significant amounts of human interleukin-6 (IL-6) and 2) parathyroid hormone-related peptide (PTHrP) into the circulation. Cancer cells further expressed mRNA for both human IL-6 and PTHrP. No secretion of human tumor necrosis factor-alpha or interleukin-1 beta could be demonstrated in the circulation of the host. Antibodies to IL-6 caused a significant (p = 0.043) inhibition of tumor growth and decreased serum calcium concentrations compared with control animals. Our data suggest that IL-6 is involved, either directly or indirectly, in the development of hypercalcemia in renal cell carcinoma.

The efficacy of diphosphonates in the treatment of diseases with increased osteoclastic bone resorption has been clearly demonstrated. Recent results show that these substances are also effective in the treatment of osteoporosis. Intermittent application of the first generation bisphosphonate, etidronate, up to three years is free of risk, stabilizes trabecular bone density after two years and seems to decrease the progression of deformations of the vertebral column in women with postmenopausal osteoporosis and vertebral fractures. In order to prove this benefit clearly, further studies of longer duration are needed. Continuous application of the second generation bisphosphonate, pamidronate, leads to an increased density of vertebral bodies in osteoporotic patients up to four years and a decreased frequency of new vertebral fractures. These results must however still be confirmed by controlled studies with more patients. There are also indications that a continuous treatment with pamidronate is able to prevent the steroid-induced bone loss. There are on the contrary no results about the effect of bisphosphonates on the fracture rate of peripheral bones and only limited results about the use of bisphosphonates in the prevention of postmenopausal bone loss. Before bisphosphonates can be offered as an alternative solution to hormone substitution therapy, we still need extensive studies about efficacy and safety.

Acute studies have been carried out with pregnant sows and their fetuses during the last 2 weeks of gestation. In blood samples obtained simultaneously it was shown that the concentrations of ionized calcium, calcitonin and parathyroid hormone (PTH) in fetal plasma were all greater than the corresponding values in maternal plasma. In contrast, the fetal concentrations of 24,25-dihydroxy vitamin D3 were lower than maternal and those of 1,25-dihydroxy vitamin D3 were not significantly different. In one experiment the circulatory level of fetal PTH was shown to be higher than in the sow by both an immunoradiometric assay and a very sensitive cytochemical assay. The latter showed the fetal: maternal ratio to be approximately three. This inappropriately high level of fetal PTH was unaffected by short term hypocalcaemic and hypercalcaemic changes in the fetal circulation. Although part of this fetal PTH may have been secreted in response to the action of beta-catecholamines released as a result of the experimental conditions, the transplacental gradient of PTH was also demonstrated in the chronically catheterized fetus. A short term period of either hypercalcaemia or hypocalcaemia induced in the mother was without consistent effect upon plasma calcium concentration in the fetus. However, an increase in ionized calcium concentration in the fetal plasma was found to follow the cessation of a period of maternal hypocalcaemia. It can be seen that the porcine fetus possesses the important elements of a calcium homeostatic mechanism, namely parathyroid hormone, calcitonin and the biologically active metabolites of vitamin D. Although the degree of independence from the mother is somewhat less than in the sheep, it is concluded that the porcine fetus is largely autonomous with respect to calcium homeostasis.