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Concept: Bisphosphonate

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Patients with multiple myeloma commonly develop focal osteolytic bone disease, as well as generalised osteoporosis. The mechanisms underlying the development of osteoporosis in patients with myeloma are poorly understood. Although disruption of the RANKL/OPG pathway has been shown to underlie formation of focal osteolytic lesions, its role in the development of osteoporosis in myeloma remains unclear. Increased soluble RANKL in serum from patients with myeloma raises the possibility that this molecule plays a key role. The aim of the present study was to establish whether sRANKL produced by myeloma cells contributes directly to osteoporosis. C57BL/KaLwRij mice were injected with either 5T2MM or 5T33MM murine myeloma cells. 5T2MM-bearing mice developed osteolytic bone lesions (p<0.05) with increased osteoclast surface (p<0.01) and reduced trabecular bone volume (p<0.05). Bone volume was also reduced at sites where 5T2MM cells were not present (p<0.05). In 5T2MM-bearing mice soluble mRANKL was increased (p<0.05), whereas OPG was not altered. In contrast, 5T33MM-bearing mice had no changes in osteoclast surface or trabecular bone volume and did not develop osteolytic lesions. Soluble mRANKL was undetectable in serum from 5T33MM-bearing mice. In separate experiments, RPMI-8226 human myeloma cells were transduced with an human RANKL/eGFP construct, or eGFP alone. RPMI-8226/hRANKL/eGFP cells, but not RPMI-8226/eGFP cells, stimulated osteoclastic bone resorption (p<0.05) in vitro. Sub-cutaneous injection of NOD/SCID mice with RPMI-8226/hRANKL/eGFP or RPMI-8226/eGFP cells resulted in tumour development in all mice. RPMI-8226/hRANKL/eGFP-bearing mice exhibited increased serum soluble hRANKL (p<0.05) and a three-fold increase in osteoclast number (p<0.05) compared to RPMI-8226/eGFP-bearing mice. This was associated with reduced trabecular bone volume (27%, p<0.05), decreased trabecular number (29%, p<0.05) and increased trabecular thickness (8%, p<0.05). Our findings demonstrate that soluble RANKL produced by myeloma cells causes generalised bone loss, suggesting that targeting RANKL may prevent osteoporosis in patients with myeloma.

Concepts: Bisphosphonate, Osteoporosis, Multiple myeloma, Bone, Osteoclast, RANKL, Osteoprotegerin, Osteoimmunology

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Osteoporosis is characterised by trabecular bone loss resulting from increased osteoclast activation and unbalanced coupling between resorption and formation, which induces a thinning of trabeculae and trabecular perforations. Bisphosphonates are the frontline therapy for osteoporosis, which act by reducing bone remodelling, and are thought to prevent perforations and maintain microstructure. However, bisphosphonates may oversuppress remodelling resulting in accumulation of microcracks. This paper aims to investigate the effect of bisphosphonate treatment on microstructure and mechanical strength. Assessment of microdamage within the trabecular bone core was performed using synchrotron X-ray micro-CT linked to image analysis software. Bone from bisphosphonate-treated fracture patients exhibited fewer perforations but more numerous and larger microcracks than both fracture and non-fracture controls. Furthermore, bisphosphonate-treated bone demonstrated reduced tensile strength and Young’s Modulus. These findings suggest that bisphosphonate therapy is effective at reducing perforations but may also cause microcrack accumulation, leading to a loss of microstructural integrity and consequently, reduced mechanical strength.

Concepts: Bisphosphonate, Osteoporosis, Multiple myeloma, Bone, Osteoclast, Materials science, Tensile strength, Solid mechanics

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Bisphosphonates are the most widely prescribed pharmacologic treatment for osteoporosis and reduce fracture risk in postmenopausal women by up to 50%. However, in the past decade these drugs have been associated with atypical femoral fractures (AFFs), rare fractures with a transverse, brittle morphology. The unusual fracture morphology suggests that bisphosphonate treatment may impair toughening mechanisms in cortical bone. The objective of this study was to compare the compositional and mechanical properties of bone biopsies from bisphosphonate-treated patients with AFFs to those from patients with typical osteoporotic fractures with and without bisphosphonate treatment. Biopsies of proximal femoral cortical bone adjacent to the fracture site were obtained from postmenopausal women during fracture repair surgery (fracture groups, n = 33) or total hip arthroplasty (nonfracture groups, n = 17). Patients were allocated to five groups based on fracture morphology and history of bisphosphonate treatment [+BIS Atypical: n = 12, BIS duration: 8.2 (3.0) y; +BIS Typical: n = 10, 7.7 (5.0) y; +BIS Nonfx: n = 5, 6.4 (3.5) y; -BIS Typical: n = 11; -BIS Nonfx: n = 12]. Vibrational spectroscopy and nanoindentation showed that tissue from bisphosphonate-treated women with atypical fractures was harder and more mineralized than that from bisphosphonate-treated women with typical osteoporotic fractures. In addition, fracture mechanics measurements showed that tissue from patients treated with bisphosphonates had deficits in fracture toughness, with lower crack-initiation toughness and less crack deflection at osteonal boundaries than that of bisphosphonate-naïve patients. Together, these results suggest a deficit in intrinsic and extrinsic toughening mechanisms, which contribute to AFFs in patients treated with long-term bisphosphonates.

Concepts: Bisphosphonate, Osteoporosis, Bone, Fracture, Fracture mechanics, Hip replacement, Orthopedic surgery, Fracture toughness

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Alendronate is a widely used bisphosphonate in the treatment of osteoporosis. Although it has been proven to be a very useful drug, it has some side effects as well. In this paper, we describe a case of nephrotic syndrome due to alendronate administration. A 36-year-old man was admitted to the nephrology outpatient clinic with widespread edema 4 months after initiation of alendronate. He had a 13-kg weight gain within a 2-week period. He had no clinical or laboratory problems apart from osteoporosis, which was the indication for initiation of the drug. Physical examination at admission was unremarkable, but for nephrotic edema. Laboratory studies revealed nephrotic range proteinuria (13.5 g/day), normal renal function, hypoalbuminemia (1.7 g/dl), and also hypercholesterolemia (400 mg/dl). A kidney biopsy was performed. Light microscopic evaluation revealed a slight increase in mesangial cells and matrix; however, no abnormalities in the tubules or interstitium were noted. Alendronate was withdrawn and diuretic therapy was initiated. Patient’s weight gradually decreased from 84 to 67 kg within a 1-week period. No other drugs for the treatment of nephrotic syndrome were administered. During the clinical course, serum creatinine remained stable, and proteinuria gradually decreased and disappeared 40 days after stopping alendronate. It was noted that alendronate administration can give rise to nephrotic syndrome, while discontinuation of this drug may improve the pathology without any specific treatment.

Concepts: Bisphosphonate, Renal failure, Kidney, Nephrology, Renal physiology, Nephrotic syndrome, Proteinuria, Nephritic syndrome

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BACKGROUND: Intravenous bisphosphonates are widely used for treatment of postmenopausal osteoporosis. They are associated with transient influenza-like symptoms, predominantly after the first zoledronic acid (up to 32 %) or ibandronate (up to 5 %) administration. The experience in clinical practice suggests that the incidence of post-dose symptoms is higher than has been reported in clinical trials. We assessed the safety of annual infusions of zoledronic acid and 3-monthly injections of ibandronate in women with postmenopausal osteoporosis. METHODS: In this retrospective study we analysed safety data from 272 postmenopausal women treated with zoledronic acid (n = 127; mean age 68.6 ± 9.4 years) or intravenous (IV) ibandronate (n = 145; mean age 69.1 ± 9.0 years). Safety data (including occurrence of acute-phase reactions and osteonecrosis of the jaw) were gathered in phone call interviews by using a standardized questionnaire. RESULTS: The number of patients with adverse events was significantly higher in zoledronic acid as compared to ibandronate-treated patients, primarily because of a larger number of post-dose symptoms after bisphosphonate administrations (54.3 % vs. 33.1 %, p < 0.001). Except for occurrence of fever (more common after zoledronic acid infusion), other influenza-like symptoms (myalgia, arthralgia, headache) appeared in a similar proportion of patients after IV treatment (within 24-36 h). Symptoms lasted for >3 days in approximately 50 % of patients. The incidence of symptoms decreased after subsequent infusions. The rate of influenza-like symptoms was more frequent after zoledronic acid than after IV ibandronate in bisphosphonate-naïve patients but comparable in patients pretreated with oral bisphosphonates. There were no spontaneous reports of osteonecrosis of the jaw, arrhythmia or delayed fracture healing. CONCLUSION: Although IV bisphosphonates are generally safe, the occurrence of transient influenza-like symptoms after IV bisphosphonates seems to be more frequent in clinical practice than has been reported in clinical trials.

Concepts: Bisphosphonate, Osteoporosis, Bisphosphonates, Multiple myeloma, Clinical trial, Bone fracture, Menopause, Adverse event

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It remains unclear whether vitamin D sufficiency optimizes response to bisphosphonate (BP) treatment in postmenopausal osteoporosis. We evaluated the role and possible mechanisms of vitamin D in adequate response to standard BP treatment for postmenopausal osteoporosis.

Concepts: Bisphosphonate, Osteoporosis, Vitamin D, Menopause

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Atypical femoral fractures (AFF) associated with long-term bisphosphonates (LTB) are a growing concern. Their aetiology is unknown but bone material properties might be deteriorated. In an AFF series, we analyzed the bone material properties by microindentation. Four groups of patients were included: 6 AFF, 38 typical osteoporotic fractures, 6 LTB and 20 controls without fracture. Neither typical osteoporotic fractures nor controls have received any antiosteoporotic medication. A general laboratory workup, bone densitometry by DXA and microindentation testing at the tibia was done in all patients. Total indentation distance (Total ID), Indentation distance increase (IDI) and Creep indentation distance (Creep ID) were measured (microns). Age-adjusted ANCOVA analysis was used for comparisons. Controls were significantly younger than fracture groups. Bisphosphonate exposure was on average 5.5 years (range 5-12) for the AFF and 5.4 years (range 5-8) for the LTB groups. Total ID (microns) showed better material properties (lower Total ID) for controls 36 (±6) (mean±SD) than for AFF 46(±4) and for typical femoral fractures 47 (±13) respectively. Patients on LTB showed values between controls and fractures, 38(±4), although not significantly different from any of the other three groups. IDI values showed a similar pattern 13 (±2), 16 (±6), 19 (±3) and 18 (±5). After adjusting by age, significant differences were seen between controls, typical (P<0.001) and atypical fractures (P=0.03) for Total ID and for IDI (P<0.001 and P<0.05 respectively). There were no differences in Creep ID between groups. Our data suggest that patients with AFF have a deep deterioration in bone material properties at a tissue level similar to that for the osteoporotic fracture group. The LTB group shows levels that are in between controls and both type of fractures although not statistically different. These results suggest that bisphosphonate therapy probably does not put the majority of patients at risk for AFF. © 2012 American Society for Bone and Mineral Research.

Concepts: Bisphosphonate, Osteoporosis, Bone, Hip fracture, Fracture, Dual energy X-ray absorptiometry, Materials science, Brittle-ductile transition zone

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Osteoporosis results in approximately one-half of older white women and one-third of men sustaining fractures, which cause significant disability and increased mortality. Interventions are now available which reduce fracture risk by about one-half, and there is evidence that they also reduce mortality in frail elderly by about 10%. The mechanism of this reduced mortality is unclear but it has the potential to substantially impact on the cost-benefit of osteoporosis treatment. Available treatments are generally well-tolerated. Bisphosphonates cause gastrointestinal side-effects when administered orally, and acute phase responses when given intravenously. Osteonecrosis of the jaw is overwhelmingly a problem of cancer sufferers rather than those with osteoporosis, but atypical patterns of fracture in the upper femoral shaft sometimes occur in users of these drugs, though they are very rare in comparison with the other osteoporotic fractures which these drugs prevent. Thus, the cost-benefit of bisphosphonate use is clearly positive in those with osteoporosis. In contrast, calcium supplements probably increase the risk of myocardial infarction, admissions to hospital with acute gastrointestinal complaints and risk of renal calculi, whereas their impact on fracture is marginal (about a 10% reduction). Thus, they are not cost-effective, and a balanced diet is a safer way of obtaining one’s calcium requirements.

Concepts: Bisphosphonate, Osteoporosis, Bone, Vitamin D, Bone fracture, Myocardial infarction, Calcium

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Low persistence with osteoporosis medication is associated with higher fracture risk. Previous studies estimated that 1-year persistence with osteoporosis medication is low. Our aim was to study persistence with osteoporosis medication among patients with long-term follow-up (to 5 years). The InterAction Database (IADB) was used to analyze persistence of 8610 Dutch patients initiating osteoporosis drugs between 2003 and 2011. Drugs under study were alendronate, risedronate, ibandronate, etidronate, raloxifene and strontium ranelate. Cumulative persistence rates were calculated after different time frames (3 months-5 years) using survival analysis. Multivariate Cox proportional hazard analyses were used to identify determinants of non-persistence. Furthermore, switching rates of persistent patients who initiated bisphosphonate therapy were analyzed. Persistence with osteoporosis therapy was 70.7 % (95 % CI, 69.7-71.7), 58.5 % (95 % CI, 57.4-59.6 %), 25.3 % (95 % CI, 24.1-26.5) after 6 months, 1 and 5 years, respectively. Determinants associated with higher risk to non-persistence within the first year were daily dosing regimen [HR, 1.76 (95 % CI, 1.46-2.14)], age <60 years [HR, 1.26 (95 % CI, 1.19-1.34)] and use of glucocorticoids [HR, 1.16 (95 % CI, 1.07-1.26)]. Monthly dosing schedule and use of generic brands of alendronate did not show a significant association with non-persistence. Approximately 4.0 % of patients initiating therapy with weekly alendronate or weekly risedronate switched therapy. Persistence with osteoporosis medication is low. Because low persistence is strongly associated with higher fracture risk, interventions to improve persistence are recommended. This study identified several patient groups in whom such interventions may be most relevant.

Concepts: Bisphosphonate, Osteoporosis, Bisphosphonates, Strontium, Proportional hazards models, Initiation, Approximation, Strontium ranelate