Drug therapy for osteoporosis in older adults.

The goal of osteoporosis management is to prevent fractures. Several pharmacological agents are available to lower fracture risk, either by reducing bone resorption or by stimulating bone formation. Bisphosphonates are the most widely used anti-resorptives, reducing bone turnover markers to low premenopausal concentrations and reducing fracture rates (vertebral by 50-70%, non-vertebral by 20-30%, and hip by ~40%). Bisphosphonates bind avidly to bone mineral and have an offset of effect measured in months to years. Long term, continuous use of oral bisphosphonates is usually interspersed with drug holidays of 1-2 years, to minimise the risk of atypical femoral fractures. Denosumab is a monoclonal antibody against RANKL that potently inhibits osteoclast development and activity. Denosumab is administered by subcutaneous injection every 6 months. Anti-fracture effects of denosumab are similar to those of the bisphosphonates, but there is a pronounced loss of anti-resorptive effect from 7 months after the last injection, which can result in clusters of rebound vertebral fractures. Two classes of anabolic drugs are now available to stimulate bone formation. Teriparatide and abaloparatide both target the parathyroid hormone-1 receptor, and are given by daily subcutaneous injection for up to 2 years. Romosozumab is an anti-sclerostin monoclonal antibody that stimulates bone formation and inhibits resorption. Romosozumab is given as monthly subcutaneous injections for 1 year. Head-to-head studies suggest that anabolic agents have greater anti-fracture efficacy and produce larger increases in bone density than anti-resorptive drugs. The effects of anabolic agents are transient, so transition to anti-resorptive drugs is required. The optimal strategy for cycling anabolics, anti-resorptives, and off-treatment periods remains to be determined.

Effect of oral zoledronate administration on bone turnover in older women.

AIM: The aim of this work is to assess the safety and efficacy of two oral zoledronate preparations by determining their effects on bone resorption in healthy postmenopausal women. METHODS: The preparations studied were zoledronic acid in enteric-coated capsules or a microparticle preparation of zoledronic acid in these capsules. Bone resorption was measured as ß-C-telopeptideof type I collagen (CTX) in fasting serum. Separate cohorts, each of five women, were recruited and allocated in sequence to single doses of 20 mg, 40 mg, or 60 mg of oral zoledronate. RESULTS: Zoledronate 20 mg enteric capsules were well tolerated, reduced serum CTX by a median 51% at 1 week, but by only 17% at 1 month. Doses of 40 or 60 mg of this preparation produced APR and/or gastrointestinal symptoms in more than half of participants. With these doses, median CTX reduction at 1 week was >80%, ~70% at 1 month, but only ~30% at 6 months. Enteric capsules containing microparticles of zoledronate 20 mg reduced CTX by a median 53% at 1 week, with offset over 3 months. Two or three of these capsules dosed weekly reduced CTX by ~50% at 1 month, and by ~30% at 3 and 6 months. CONCLUSIONS: Oral zoledronate 20 mg circumvents the problem of APR symptoms but, even with multiple doses, the anti-resorptive effect is smaller and less sustained than with intravenous zoledronate. Probably a viable oral regimen of zoledronate dosing at intervals of weeks to months could be developed, but the advantage of infrequent dosing would be lost.

Asia-pacific consensus on osteoporotic fracture prevention in postmenopausal women with low bone mass or osteoporosis but no fragility fractures.

Postmenopausal women are at significant risk for osteoporotic fractures due to their rapid bone loss. Half of all postmenopausal women will get an osteoporosis-related fracture over their lifetime, with 25% developing a spine deformity and 15% developing a hip fracture. By 2050, more than half of all osteoporotic fractures will occur in Asia, with postmenopausal women being the most susceptible. Early management can halt or even reverse the progression of osteoporosis. Consequently, on October 31, 2020, the Taiwanese Osteoporosis Association hosted the Asia-Pacific (AP) Postmenopausal Osteoporotic Fracture Prevention (POFP) consensus meeting, which was supported by the Asian Federation of Osteoporosis Societies (AFOS) and the Asia Pacific Osteoporosis Foundation (APOF). International and domestic experts developed ten applicable statements for the prevention of osteoporotic fractures in postmenopausal women with low bone mass or osteoporosis but no fragility fractures in the AP region. The experts advocated, for example, that postmenopausal women with a high fracture risk be reimbursed for pharmaceutical therapy to prevent osteoporotic fractures. More clinical experience and data are required to modify intervention tactics.

Fracture Prevention with Zoledronate in Older Women with Osteopenia.

BACKGROUND: Bisphosphonates prevent fractures in patients with osteoporosis, but their efficacy in women with osteopenia is unknown. Most fractures in postmenopausal women occur in those with osteopenia, so therapies that are effective in women with osteopenia are needed. METHODS: We conducted a 6-year, double-blind trial involving 2000 women with osteopenia (defined by a T score of -1.0 to -2.5 at either the total hip or the femoral neck on either side) who were 65 years of age or older. Participants were randomly assigned to receive four infusions of either zoledronate at a dose of 5 mg (zoledronate group) or normal saline (placebo group) at 18-month intervals. A dietary calcium intake of 1 g per day was advised, but calcium supplements were not provided. Participants who were not already taking vitamin D supplements received cholecalciferol before the trial began (a single dose of 2.5 mg) and during the trial (1.25 mg per month). The primary end point was the time to first occurrence of a nonvertebral or vertebral fragility fracture. RESULTS: At baseline, the mean (±SD) age was 71±5 years, the T score at the femoral neck was -1.6±0.5, and the median 10-year risk of hip fracture was 2.3%. A fragility fracture occurred in 190 women in the placebo group and in 122 women in the zoledronate group (hazard ratio with zoledronate, 0.63; 95% confidence interval, 0.50 to 0.79; P<0.001). The number of women that would need to be treated to prevent the occurrence of a fracture in 1 woman was 15. As compared with the placebo group, women who received zoledronate had a lower risk of nonvertebral fragility fractures (hazard ratio, 0.66; P=0.001), symptomatic fractures (hazard ratio, 0.73; P=0.003), vertebral fractures (odds ratio, 0.45; P=0.002), and height loss (P<0.001). CONCLUSIONS: The risk of nonvertebral or vertebral fragility fractures was significantly lower in women with osteopenia who received zoledronate than in women who received placebo. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12609000593235 .).

Effect of Zoledronate on Lower Respiratory Infections in Older Women: Secondary Analysis of a Randomized Controlled Trial.

A recent observational study of the incidence of pneumonia in patients with previous hip fractures found that bisphosphonate use reduced pneumonia risk by about one-quarter, in comparisons with those either not receiving osteoporosis treatment or receiving treatment with non-bisphosphonate drugs. Mortality from pneumonia was similarly reduced. It was hypothesized that effects of these drugs on immune or inflammatory function might mediate this effect. We have used the adverse event database from our recent 6-year randomized controlled trial of zoledronate in 2000 women over the age of 65 years, to determine whether a similar effect is observed using this more rigorous study design. Seventy-five women had at least one episode of pneumonia (32 [3.2%] zoledronate, 43 [4.3%] placebo) and 119 women had at least one episode of either pneumonia or a lower respiratory tract infection (57 [5.7%] zoledronate, 62 [6.2%] placebo). There were 93 pneumonia events and 167 pneumonia/lower respiratory infection events. For pneumonia, the hazard ratio associated with randomization to zoledronate was 0.73 (95% confidence interval, 0.46-1.16; P = 0.18) and the rate ratio was 0.69 (0.45, 1.04; P = 0.073). For the composite endpoint of pneumonia or lower respiratory infection, the hazard ratio was 0.90 (0.61, 1.30; P = 0.58) and the rate ratio 0.74 (0.54, 0.997; P = 0.048). The proportion of people with events changed approximately linearly over time in both groups, suggesting a progressive divergence in cumulative incidence during the study. In conclusion, these findings lend support to the hypothesis that bisphosphonate use reduces the number of lower respiratory tract infections in older women, though the present study is under-powered for this endpoint and the findings are of borderline statistical significance. Further analysis of other trials of bisphosphonates is necessary to test this possibility further, and exploration of the possible underlying mechanisms is needed.

Zoledronate Slows Weight Loss and Maintains Fat Mass in Osteopenic Older Women: Secondary Analysis of a Randomized Controlled Trial.

Studies in mice have suggested that osteocalcin plays an important role in glucose and fat metabolism. Since anti-resorptive drugs reduce circulating levels of osteocalcin they might be associated with increased fat mass and an increased risk of diabetes. Positive changes in body weight have been found in trials of alendronate and denosumab, but no significant effect in a previous trial of zoledronate. Whether those weight differences were in fat or lean mass is unknown. There were no effects of anti-resorptive treatments on fasting glucose concentrations or incidence of diabetes in those three studies. We have used our recent trial comparing zoledronate and placebo over 6 years in 2000 older osteopenic women to re-examine these questions. Both treatment groups lost body weight during the study (placebo 1.65 kg, zoledronate 1.05 kg), and this was significantly greater in the placebo group (P = 0.01). Both groups lost lean mass, and this loss was marginally (0.17 kg) but significantly (P = 0.02) greater in those receiving zoledronate. The placebo group had a mean loss of fat mass of 0.63 kg but there was no change in fat mass in the zoledronate group (between-groups comparison, P = 0.007). In the placebo group, there were 20 new diagnoses of diabetes, and in the zoledronate group, 19 (P = 0.87). Zoledronate prevented age-related loss of fat mass in these late postmenopausal women. The present study is the first to document a significant effect of zoledronate treatment on body weight, confirming results previously found with alendronate and denosumab. It also demonstrates that this is principally an effect to maintain fat mass rather than influencing lean mass, raising an important physiological question as to how anti-resorptive drugs have this effect on intermediary metabolism. It is possible that this anti-catabolic action contributes to the beneficial effects of anti-resorptive drugs on bone and longevity.

Benefits of Bisphosphonate Therapy: Beyond the Skeleton.

PURPOSE OF REVIEW: Recent evidence from clinical trials and observational studies raises the possibility that bisphosphonate use might confer a lower risk of cardiovascular disease and cancer, resulting in a mortality benefit. This review summarizes clinical and preclinical studies examining the non-skeletal effects of bisphosphonates. RECENT FINDINGS: Data from clinical trials are conflicting regarding whether or not bisphosphonates have beneficial effects on mortality, cardiovascular events, or cancer incidence. No clinical trials have assessed these outcomes as primary endpoints, and most trials were shorter than 4 years. Observational data suggest that bisphosphonate users may have lower mortality, delayed progression of vascular calcification and atherosclerotic burden, and reduced incidence of breast and colorectal cancer compared to non-users. Preclinical studies confirm that bisphosphonates can be taken up by macrophages and monocytes, and nitrogen-containing bisphosphonates have the ability to disrupt the mevalonate pathway within these cells. In this manner, bisphosphonates exert anti-atherogenic and anti-cancer effects. Bisphosphonates also appear to exert protective effects on vascular smooth muscle cells and endothelial cells and may have direct cytotoxic effects on cancer cells. The balance of evidence does not support bisphosphonate treatment for the primary purpose of improving non-skeletal outcomes, although appropriately designed controlled trials that further explore this possibility are both justified and required. Patients with skeletal indications for bisphosphonate therapy can be reassured that these agents are not associated with increased mortality, cardiovascular disease, or cancer incidence.

Calcium and Bone.

The maintenance of extracellular calcium levels within a narrow range is necessary for normal function of the nervous system, muscle, and coagulation, to maintain mineralization of the skeleton but to avoid calcification of soft tissues. Accordingly, absorption and excretion of calcium is closely regulated, and adult humans can adapt to a wide range of calcium intakes from 300 to 2,000 mg/day. The evidence that low calcium intakes contribute to osteoporosis development is weak, as is evidence that increasing these intakes significantly changes fracture risk. Consistent with this view, the United States Preventive Services Task Force does not support the use of calcium supplements in healthy community-dwelling adults. While some groups continue to recommend that supplements of calcium and vitamin D are given with drug treatments for osteoporosis, this view is not supported by clinical trials which demonstrate anti-fracture efficacy of estrogens and bisphosphonates in the absence of such supplementation. Thus, calcium supplements have only a minor place in contemporary medical practice.

Fibroblast growth factor 23 levels decline following sleeve gastrectomy.

OBJECTIVE: Levels of fibroblast growth factor 23 (FGF23) have been positively associated with measures of adiposity, cardiovascular disease and mortality. It is unclear whether the relationship of FGF23 with cardiovascular disease and mortality is confounded by obesity. We aimed to determine whether FGF23 concentrations decline following a reduction in adiposity after sleeve gastrectomy (SG). DESIGN: The effect of SG on FGF23 was evaluated in 22 obese adults (59% male) with type 2 diabetes. Fat mass, weight, BMI, plasma intact FGF23, parathyroid hormone (PTH) and leptin were determined at baseline and at 12 months following SG. RESULTS: At baseline, median (IQR) age was 51 (43-54) years, fat mass 47.8 (41.0-59.4) kg, BMI 40.9 (36.9-46.9) kg/m2 and FGF23 66.2 (55.3-82.9) pg/mL. Significant changes in median BMI (-10.8 kg/m2 , 95% CI: -12.9 to -7.2, P < 0.0001), fat mass (-20.0 kg, 95% CI: -26.7 to -12.4, P < 0.0001) and weight (-34.7 kg, 95% CI -40.0 to -23.1, P < 0.0001) were observed after SG. FGF23 (-12.4 pg/mL, 95% CI: -19.5 to 2.0, P = 0.005), PTH (-1.1 pmol/L, 95% CI: -1.7 to 0.2, P = 0.009) and leptin (-1687 pg/mL, 95% CI -4524 to -563, P = 0.01) declined following SG. Change in FGF23 was not significantly associated with change in measures of adiposity, PTH or leptin. CONCLUSIONS: FGF23 concentrations decline in the setting of significant weight loss following SG, implying that increased FGF23 concentrations are a downstream consequence of obesity, which may confound its association with cardiometabolic dysfunction. Mediators of the relationship between adiposity and FGF23 require further elucidation.

Bone-Bound Bisphosphonates Inhibit Proliferation of Breast Cancer Cells.

Bisphosphonates are used in treating patients with breast cancer. In vitro studies have shown that bisphosphonates act directly on tumour cells, inhibiting cell proliferation and inducing apoptosis. In most such studies, drugs were added to culture media exposing cells to high bisphosphonate concentrations in solution. However, since bisphosphonates bind to bone hydroxyapatite with high affinity and remain bound for very long periods of time, these experimental systems are not an optimal model for the action of the drugs in vivo. The aim of this study was to determine whether bone-bound zoledronate has direct effects on adjacent breast cancer cells. Bone slices were pre-incubated with bisphosphonate solutions, washed, and seeded with cells of the breast cancer cell lines, MCF7 or MDA-MB-231. Proliferation was assessed by cell counts and thymidine incorporation for up to 72 h. Inhibition of the mevalonate pathway was tested by measuring the levels of unprenylated Rap1A, and apoptosis was examined by the presence of cleaved caspase-8 on western blots. The proliferation rate of breast cancer cells on zoledronate-treated bone was significantly lower compared to cells on control bone. Other bisphosphonates showed a similar inhibitory effect, with an order of potency similar to their clinical potencies. Unprenylated Rap1A accumulated in MCF7 cells on zoledronate-treated bone, suggesting zoledronate acted through the inhibition of the mevalonate pathway. Accumulation of cleaved caspase-8 in MDA-MB-231 cells on bisphosphonate-treated bone indicated increased apoptosis in the cells. In conclusion, bone-bound zoledronate inhibits breast cancer cell proliferation, an activity that may contribute to its clinical anti-tumour effects.

Long-Term Stable Bone Mineral Density in HIV-Infected Men Without Risk Factors for Osteoporosis Treated with Antiretroviral Therapy.

INTRODUCTION: Most prospective studies of bone mineral density (BMD) in HIV-infected cohorts taking antiretroviral therapy (ART) have been of short duration, typically < 3 years. Such studies have reported short-term stable or increasing BMD. We assessed whether this BMD stability persists for > 10 years in middle-aged and older men established on ART. METHODS: A 12-year, prospective, longitudinal study in 44 HIV-infected men treated with ART who had measurements of BMD at the lumbar spine, proximal femur and total body at baseline, 2, 6 and 12 years. RESULTS: At baseline, the mean age of participants was 49 years, the mean duration of HIV infection was 8 years, and the mean duration of ART was 50 months. After 12 years, BMD increased by 6.9% (95% CI 3.4 to 10.3) at the lumbar spine, and remained stable (range of BMD change: - 0.6% to 0.0%) at the total hip, femoral neck and total body. Only two individuals had a decrease of > 10% in BMD at any site during follow-up and both decreases in BMD were explained by co-morbid illnesses. CONCLUSIONS: BMD remained stable over 12 years in middle-aged and older HIV-infected men treated with ART. Monitoring BMD in men established on ART who do not have risk factors for BMD loss is not necessary.

Controversies in medicine: the role of calcium and vitamin D supplements in adults.

Vitamin D is made in the skin when exposed to sunlight, so deficiency is usually the result of low sunlight exposure (eg, in frail older people and in individuals who are veiled). Calcium and/or vitamin D supplements have been used for the prevention and treatment of osteoporosis. The major trials in community-dwelling individuals have not demonstrated fracture prevention with either calcium, vitamin D, or their combination, but the results of a large study in vitamin D-deficient nursing home residents indicated a reduced fracture incidence. Trials show that vitamin D increases bone density when winter 25-hydroxyvitamin D levels are below 25-30 nmol/L. However, assay expense and variability suggest that supplements are better targeted based on clinical status to frail older people and possibly to people with dark skin living at higher latitudes. A daily dose of 400-800 units (10-20 µg) is usually adequate. Parenteral antiresorptive drugs can cause hypocalcaemia in severe vitamin D deficiency (< 25 nmol/L), which should therefore be corrected before treatment. Clinical trials have not demonstrated benefits of vitamin D on non-skeletal endpoints. Calcium supplements in healthy individuals are not needed, nor are they required in most people receiving treatment for osteoporosis, where they have not been shown to affect treatment efficacy. Calcium supplements cause constipation, bloating and kidney stones, and some evidence suggests they may cause a small increase in the risk of myocardial infarction. Low dose vitamin D is safe, but high doses result in more falls and fractures. Current evidence does not support the use of these supplements in healthy community-dwelling adults.

Bone Loss After Romosozumab/Denosumab: Effects of Bisphosphonates.

Romosozumab and denosumab are monoclonal antibodies for the treatment of osteoporosis. Both have a rapid offset of effect resulting in loss of bone density (BMD) gained on-treatment and, in some cases, multiple vertebral fractures following treatment cessation. We recently reported disappointing results from transitioning patients from denosumab to intravenous zoledronate at the time the next denosumab injection is due. The present report re-assesses the role of bisphosphonates following the use of denosumab. In the FRAME trial, osteoporotic women were randomized to romosozumab or placebo for 1 year, then both groups were provided with open-label denosumab for the subsequent 2 years. In women completing this study at our center, we offered treatment with either oral or intravenous bisphosphonates. In the eleven women opting for intravenous treatment, zoledronate was given after a median delay of 65 days from trial-end, in the hope that this might increase skeletal uptake of the drug and, thereby, its efficacy to maintain bone density. In these women, spine BMD was 17.3% above baseline at trial-end, and still 12.3% above baseline a year later, a 73% (CI: 61%, 85%) retention of the treatment benefit. The comparable BMD figures for the total hip were 10.7 and 9.2% above baseline, a 87% (CI: 77%, 98%) retention of treatment effect. In contrast, those not receiving treatment after the conclusion of the FRAME trial lost 80-90% of the BMD gained on-trial in the following 12 months. Women treated with risedronate showed an intermediate response. In the zoledronate group, mean PINP 6 months post-FRAME was 23 ± 4 µg/L and at 12 months it was 47 ± 8 µg/L, suggesting that repeat zoledronate dosing is needed at 1 year to maintain the BMD gains. In conclusion, delaying administration of intravenous bisphosphonate when transitioning from short-term denosumab appears to increase the extent to which the gains in BMD are maintained.

Lack of Evidence that Soluble Urate Directly Influences Bone Remodelling: A Laboratory and Clinical Study.

INTRODUCTION: Numerous observational studies have reported that serum urate concentration positively correlates with bone density and reduced risk of fractures. The aim of this study was to examine whether soluble urate directly influences bone remodelling. METHODS: In laboratory studies, the in vitro effects of soluble urate were examined in osteoclast, osteoblast and osteocyte assays at a range of urate concentrations consistent with those typically observed in humans (up to 0.70 mmol/L). The clinical relevance of the in vitro assay findings was assessed using serial procollagen-1 N-terminal propeptide (P1NP) and Month 12 bone density data from a randomised controlled trial of allopurinol dose escalation in people with gout. RESULTS: Addition of urate in the RAW264.7 cell osteoclastogenesis assay led to small increases in osteoclast formation (ANOVA p = 0.018), but no significant difference in bone resorption. No significant effects on osteoclast number or activity were observed in primary cell osteoclastogenesis or resorption assays. Addition of urate did not alter viability or function in MC3T3-E1 pre-osteoblast, primary human osteoblast, or MLO-Y4 osteocyte assays. In the clinical trial analysis, reducing serum urate over a 12 month period by allopurinol dose escalation did not lead to significant changes in P1NP or differences in bone mineral density. CONCLUSION: Addition of soluble urate at physiological concentrations does not influence bone remodelling in vitro. These data, together with clinical trial data showing no effect of urate-lowering on P1NP or bone density, do not support a direct role for urate in influencing bone remodelling.

Serum phosphate is related to adiposity in healthy adults.

BACKGROUND: Inorganic phosphate is a crucial component of cellular energy metabolism. We have identified an inverse relationship between serum phosphate concentration and fat mass in a cohort of healthy men. This study reports those data and determines whether this association is present in two female populations. METHODS: Cross-sectional data from three independent cohorts, consisting of healthy adult males (Male Cohort, n = 323) and healthy postmenopausal women (Female Cohort 1, n = 185; and Female Cohort 2, n = 1471), are reported. Associations between serum phosphate and weight, body mass index (BMI), fat mass and bone mineral density (BMD) were assessed. In a fourth cohort of postmenopausal women (FGF23 Cohort, n = 20), associations between fibroblast growth factor 23 (FGF23), weight and BMI were assessed. RESULTS: Serum phosphate correlated inversely with weight, BMI and fat mass across all three cohorts (r = -0·13 to -0·31, P < 0·0001-0·02). Associations were diminished after adjustment for PTH, but remained significant. In the FGF23 Cohort, FGF23 was positively correlated with weight (r = 0·60, P = 0·007) and BMI (r = 0·49, P = 0·03). Phosphate was inversely associated with BMD in Female Cohorts 1 and 2 (r = -0·08 to -0·29, P < 0·0001-0·02). This relationship was attenuated, but remained significant at most sites, following adjustment for age, fat mass, renal function and 25-hydroxyvitamin D. CONCLUSIONS: Serum phosphate is inversely associated with measures of adiposity in both women and men, largely independently of PTH. FGF23 might mediate these associations. This relationship may be an unrecognized confounder in some of the correlates of serum phosphate already described.

Long-Term Bone Scintigraphy Results After Intravenous Zoledronate in Paget's Disease of Bone.

Zoledronate produces long-term normalization of biochemical markers in Paget's disease but whether this implies the absence of active disease is unknown. We have determined whether bone scintigraphy, a more sensitive index of disease activity, is also normalized ≥5 years after treatment with zoledronate. A consecutive case series of 11 individuals with Paget's disease treated with zoledronate 5 mg ≥5 years previously is reported. Eight patients received a single zoledronate infusion and were assessed 55-120 months later. Bone scintigraphy showed no evidence of active disease in four of these patients, and there was minimal residual disease activity in the other four. Three other patients required second infusions because of evidence of ongoing disease activity. In two of these, scintigraphy was normal ~90 months after their second infusions. In the third, further follow-up is not available. Procollagen-I N-terminal propeptide and total alkaline phosphatase were normal in all subjects at the time of bone scintigraphy. This case series confirms the high rate of response of Paget's disease to zoledronate, demonstrates the much greater sensitivity of scintigraphy compared with biochemical markers in detecting ongoing disease activity, and indicates that about one-third may be scintigraphically "cured" after one infusion; one-third have scintigraphically trivial disease activity subsequently, and the balance may require a second infusion. Scintigraphic "cure" is achievable after second infusions. Scintigraphy has an important place in the long-term management of Paget's patients following zoledronate, and should guide follow-up decisions in those with normal biochemical markers.

Bone Loss After Denosumab: Only Partial Protection with Zoledronate.

A case series of six women with postmenopausal osteoporosis who had received continuous denosumab for 7 years and were then given a single infusion of zoledronate (5 mg) is reported. During denosumab treatment, bone mineral density (BMD) in the spine increased 18.5% (P = 0.006), and total hip BMD by 6.9% (P = 0.03). Post-zoledronate BMDs were measured 18-23 months after treatment, and there were significant declines at each site (P spine = 0.043, P hip = 0.005). Spine BMD remained significantly above the pre-denosumab baseline (+9.3%, P = 0.003), but hip BMD was not significantly different from baseline (-2.9%). At the time of post-zoledronate BMD measurements, serum PINP levels were between 39 and 60 µg/L (mean 52 µg/L), suggesting that the zoledronate treatment had not adequately inhibited bone turnover. It is concluded that this regimen of zoledronate administration is not adequate to preserve the BMD gains that result from long-term denosumab treatment.

Long-Term Effects of Intravenous Ibandronate in Paget's Disease of Bone.

We have previously demonstrated that intravenous ibandronate produces high initial response rates in Paget's disease, but the durability of this effect is unknown. It might be expected to be short lived because ibandronate has a low affinity for bone. Here we report long-term follow-up (up to 14 years) of patients from that trial. Twenty-five patients with active Paget's disease [baseline serum total alkaline phosphatase (ALP) ~3 times the upper limit of normal] received either 6 or 12 mg intravenous ibandronate at baseline. There were prompt reductions in ALP following treatment, with normalization in 88%. ALP remained in the normal range in most patients for 20-30 months, but some subjects then showed gradual increases. Three years after ibandronate, before any patients had received additional treatment, ALP was normal in 61%. Six patients maintained normal ALP beyond 6 years without further intervention. Responses to 6 and 12 mg were similar. These results indicate that long-term remissions in Paget's disease can be achieved with bolus delivery of a potent bisphosphonate, even if the drug has a low affinity for bone. Therefore, bisphosphonate retention in bone might not be the only factor determining duration of remission. Intravenous bisphosphonates are likely to produce high drug concentrations within pagetic lesions which might result in cytotoxicity to the pagetic cells, leading to long durations of remission. These findings strengthen the evidence that potent bisphosphonates delivered in a single intravenous dose are a very efficient way to manage this condition.