Overview, Vol 9, Issue 3

Arrthymias and osteoporosis treatment – cause or coincidence?

Arrthymias and osteoporosis occur in elderly persons so the possibility that the association between atrial fibrillation and bisphosphonate use, particular using zolendronic acid is the result of coincidence of aging of bone and heart. Heckbert et al reported a population-based case-control study and identified 719 women with AF and 966 controls without AF, selected at random, matched on age and blood pressure. More cases with AF than controls had ever used alendronate (6.5% [n=47] vs. 4.1% [n=40]; P=0.03) producing an odds ratio of 1.86 (95% CI 1.09-3.15) after adjustment. Arch Intern Med 2008;168:826-31

This data is difficult to interpret give that case control methodology is not a high level of evidence based medicine. Compare this study with the data reported by Sorenson et al (2008) who report no greater exposure to etidronate or alendronate among 13586 cases with AF then 68054 controls. Where does truth lie?

Microdamage and bisphosphonate, a challenge to understand

Bone toughness, a tissues capacity to absorb energy is reduced using bisphosphonates. Allen et al studied beagle rib morphology. Three years alendronate 0.2 or 1.0 mg/kg reduced toughness with the higher dose (above that used in osteoporosis in women/kg basis) (Calcif Tissue Int 2008 [Epub ahead of print]). Neither ultimate stress nor modulus differed relative to controls. There was no difference in overall microdamage accumulation. The data support a dose related effect on bone quality. Microdamage occurrence might be region specific, depending on loadings circumstances. These drugs are pretty safe, but not always, and the effects are likely to depend on dose, duration of therapy, region,  features in the species treated such as bone remodeling rate, level and duration of suppression.

Bisphosphonate action

There are not many beautifully written works of art in the scientific literature. If you are interested to see what can be achieved if time is taken to construct a work of art then read this by Russell and his colleagues: Osteoporos Int 2008;19:733-59

Mineral binding affinities differ among the BPs and may influence their differential distribution within bone, their potency, and duration of action. The nitrogen-containing BPs inhibit farnesyl pyrophosphate synthase in osteoclasts, an enzyme in the mevalonate pathway that generates isoprenoid lipids used for modification of GTP-binding proteins needed for osteoclast function. Each BP has a unique profile that may help to explain clinical differences in speed and duration of action, and effects on fracture reduction.

Are all bisphosphonates the same – of course not

Fuchs et al gave alendronate (ALN) and risedronate (RIS) to 6-month old OVX rats. Turnover were similarly to a similar extent – not more greatly with alendronate, but 16 weeks after withdrawal, trabecular BFR/BS in the proximal tibia was reestablished post-RIS, not post-ALN, relative to controls (but not clearly differently relative to each other). BMD of the 5th lumbar vertebra remained higher than controls post-ALN, not post-RIS. J Bone Miner Res 2008 [Epub ahead of print]

The notion that ALN suppresses remodeling more than RIS is not at all well founded but is widely accepted as such, mainly based on the FACT trial (Rosen et al, 2005), a study that is difficult to interpret for a range of reasons. However, the evidence of persistent suppression with ALN over RIS following cessation of treatment has a better evidence base – is this a good thing or bad thing?

Anti-resorptives – new opportunities for dissociating resorption and formation

Estrogen deficiency is mediated by cytokines such as TNFalpha and IL-1. The p38 pathway mediates cytokines effects so the selective p38alpha inhibitor, SD-282, was assessed during 8 weeks by Caverzasio et al and found to blunt increase in DPD/Cr induced by OVX in adult rats. SD-282 enhanced by two-fold the rise in serum osteocalcin, blocked vertebral bone loss, reduced trabecular bone loss in long bones, and enhanced cross sectional area rise of the diaphysis. Whether this opens doors to differing action of drugs on bone formation and resorption is difficult to say, markers of ‘formation’ and ‘resorption’ are not the same as histological evidence of resorption at the tissue and cellular (BMU) levels. J Bone Miner Res 2008 [Epub ahead of print]

PTH and raloxifene

Cosman et al report that 42 women receiving raloxifene either continued it or one group had 1-34PTH daily added for 12 months and then were followed for 12 months on raloxifene alone. Biochemical indices and BMD increased during PTH, except BMD declined in the radius. From this design it is not possible to conclude whether blunting of the PTH has occurred by raloxifene as there is no PTH-alone group. After PTH withdrawal, BMD declined but increased at femoral neck. At 24 months, spine and femoral neck BMD remained higher than baseline, while radius BMD remained lower. Gains in BMD of the spine and hip, and loss at the radius, are seen with PTH. While the authors conclude raloxifene partially maintains PTH gains, this is difficult to infer without a group receiving PTH alone, then stopping the PTH. Osteoporos Int 2008;19:529-35

RANKL inhibition with osteoprotegerin

Ominsky et al report that OVX rats treated with human OPG-Fc had reduced osteoclast surface and serum TRACP5b with prevention OVX-associated bone loss. Vertebrae had increased dry and ash weight, with no differences in tissue mineralization. Micro-CT showed higher trabecular bone volume fraction, vBMD, bone area, trabecular thickness, and number; whereas their cortical compartments had greater bone area. OPG improved cortical area in L(5) and the femur neck to levels that were greater than sham controls. L(5) and femur necks showed greater maximum load versus OVX. J Bone Miner Res 2008;23:672-82

Osteopenia and fracture prevention with risedronate

Siris et al report that 620 postmenopausal women with osteopenia and no prevalent vertebral fractures were identified from BMD Multinational, BMD North America, VERT Multinational and VERT North America trials. 309 received placebo, 311 received risedronate 5 mg. Risedronate reduced the risk of fragility fractures by 73% over 3 years vs. placebo (p=0.023); cumulative fragility fracture incidence was 6.9% in placebo-treated vs. 2.2% in risedronate-treated patients. While this may be the case, selection according to osteopenia at the proximal femur leaves the possibility that a proportion of these patients had osteoporosis at the spine. Osteoporos Int 2008;19:681-6

Calcium and vitamin D, the dynamic duo?

Nieves et al report that in 76,507 postmenopausal Caucasian women, vitamin D intake was calculated from milk, fish, supplements and sunlight exposure. Three years later, 36,209 participants returned a questionnaire about new fractures. Women reported 2,205 new osteoporosis-related fractures. The 3-year risk of fracture was not associated with intake of calcium or vitamin D. Osteoporos Int 2008;19:673-9

Osteoblast death and aminobisphosphates

It is not commonly appreciated that the main effect of anti-resorptive agents is through the inhibition of the birthrate of new remodeling units. This effect is responsible for the reduction in the surface extent of bone resorption and later surface extent of bone formation. Idris et al report that pamidronate and alendronate inhibited osteoblast growth, caused osteoblast apoptosis, and inhibited protein prenylation in osteoblasts. Alendronate inhibited protein prenylation in calvarial osteoblasts in vivo. Interestingly, pamidronate and alendronate inhibited nodule formation at low concentrations without affecting osteoblast growth, apoptosis or differentiation. Calcif Tissue Int 2008;82:191-201

SERM on basedoxifene

Miller et al report that bazedoxifene 10, 20, or 40 mg/d and raloxifene 60 mg/d studied in 1434 women (mean age, 58 yr) prevented bone loss, decreased serum osteocalcin and C-telopeptide. Bazedoxifene prevented bone loss and reduced turnover as well as raloxifene and was well tolerated. The outstanding issue with SERMs is whether they can reduce nonvertebral fractures. J Bone Miner Res 2008;23:525-35

Zoledronic acid versus alendronate in rats

Gasser et al compared single intravenous doses of ZOL 0.8, 4, 20, 100, 500 µg/kg, alendronate 200 µg/kg before OVX for 32 wk. OVX-associated BMD loss was attenuated by ZOL. Alendronate 200 µg/kg was of equivalent to ZOL 20 µg/kg. OVX-associated decreases in trabecular architectural parameters were attenuated by ZOL. Alendronate 200 µg/kg was equivalent to ZOL 20 µg/kg. Bone formation parameters were reduced by ZOL 100-500 µg/kg. Alendronate 200 µg/kg was equivalent to ZOL 100 µg/kg. Alendronate 200 ug/kg was of similar potency to ZOL 20 µg/kg. Compared with alendronate, ZOL shows 10-fold higher potency in preventing bone loss. J Bone Miner Res 2008;23:544-51

Adhere, persist, comply or fracture

Rabenda et al report the serious consequences of poor compliance at 12 months. The medication possession ratio (MPR) at 12 months was higher among patients receiving weekly (n=15,021, 70.5%) compared to daily alendronate (n=14,136, 58.6%;). At 12 months, persistence was 39.45%. For each decrease of the MPR by 1%, the risk of hip fracture increased by 0.4%. The relative risk reduction for hip fracture was 60% (HR: 0.404; 0.357-0.457) for persistent compared to nonpersistent patients. Osteoporos Int 2008;19: 811-8

Genetics

The great benefit of genetic research is the discovery of pathways in bone biology, rewriting the text books. In terms of identifying individuals at risk for fracture or specific treatment approaches there is little if any contribution because the proportion of trait variance attributable to a single of genetic polymorphism is small.

Ri​chards et al report an association between a SNP in the LRP5 gene was associated with decreased BMD for femoral neck and an increased risk of fractures (OR 1.3, 1.09-1.52) and osteoporosis (OR 1.3, 1.08-1.63, p=0.008). 314,075 SNPs were identified in 2094 women and tested for replication in 6463 people for association with fractures. SNPs rs4355801 on chromosome 8, near to the osteoprotegerin gene, and rs3736228, on chromosome 11 in the LRP5 gene were found. Three SNPs near the TNFRSF11B gene were associated with decreased BMD and risk of osteoporosis (OR 1.2, 1.01-1.42). The presence of both increased the risk of fractures (OR 1.3, 1.08-1.63, p=0.006). Lancet 2008; 371:1505-12

Styrkarsdottir et al tested 5861 subjects for 301,019 SNPs and BMD. Association between 74 SNPs at 32 loci in Icelandic, Danish and Australian subjects showed associations. Three regions close to (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). Two regions close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were associated with fractures, as were loci at 18q21, close to the RANK gene and loci at 2p16 and 11p11. N Engl J Med 2008 [Epub ahead of print]

FRAX….ing lyrical

FRAX has arrived. It may appear to be salvation, the answer to uncertainty, but that is unlikely because the decision to treat or not to treat will always be difficult in some situations. There will be no magic formula to tell us what is high risk or low risk – and so when to and not to treat. Is a 1% in 10 years high or low risk? Is 10% in 10 high – i.e., 1 in 100 people in your office will fracture – which one will it be? Sounds like pretty low odds but in medicine a 1-3% per year risk is the sort of risk present in clinical trials. Kanis et al construct 4 models comprising the 10-year probability of hip fracture, with and without femoral neck BMD, and the 10-year probability of a major osteoporotic fracture, with and without BMD. In the absence of BMD, hip fracture probability in women with a fixed BMI (25 kg/m2) ranged from 0.2% at 50 years for women without risk factors to 22% at 80 years with a parental history of hip fracture (~100-fold range). In men, the probabilities were lower, as was the range (0.1-11% in the examples above). For a major osteoporotic fracture the probabilities ranged from 3.5-31% in women, and from 2.8-15% in men in the example above. Osteoporos Int 2008;19:385-97

Kanis et al provide a comprehensive set of guidelines in a European setting on the assessment and treatment of postmenopausal women with or at risk from osteoporosis reviewing the role of BMD measurement for the diagnosis of osteoporosis and assessment of fracture risk, management of osteoporosis, monitoring of treatment, assessment of fracture risk, case finding strategies investigation and health economics of treatment. Osteoporos Int 2008;19:399-428

Osteocyte – the first among equals

The first event in bone remodeling is not known. The growing awareness of the osteocyte as the likely conductor of the orchestral concert of bone remodeling is an exciting advance in our understanding and Dr. Noble has made important contributions in this area. Kogianni et al report that osteocyte apoptosis precedes osteoclastic bone resorption, apoptotic osteocytes support osteoclastogenesis and osteoclastic bone resorption in vivo and in vitro and increase osteoclastic resorption. indicating that the site-specific apoptotic death of osteocytes underlies the mechanism by which targeted remodeling is initiated in bone. J Bone Miner Res 2008 [Epub ahead of print]

Remodeling balance and bone gain and loss

There are excellent lessons here. Tian et al gave 6-month-old female rats PGE(2). Continuous or intermittent PGE(2). Both routes stimulated bone remodeling, but continuous PGE(2) produced a negative BMU balance causing cancellous bone loss and shortened the formation period and cortical bone loss because the negative endocortical bone balance and increased intracortical porosity bone loss was greater than periosteal bone gain. Intermittent PGE(2) increased cancellous bone by positive balance from stimulated bone formation and shortened resorption period; while cortical bone gain occurred from endocortical bone gain exceeding the decrease in periosteal bone and increased intracortical bone loss. Bone 2008;42:914-20

Men and fractures, uncommon, hard to identify

Freitas et al report some challenges in fracture prevention in men. 5995 men were followed for about 5 years. Only 1% sustained incident clinical vertebral fractures (2.2/1,000 person-years; 0.7% in men 65-69 years and 5% ≥85 years. Most with incident fractures did not have osteoporosis. Osteoporos Int 2008;19:615-23

Men neglected

Men with osteoporosis are still not treated. One legal case will solve this problem. Papaioannou et al followed 2187 men and report diagnosis and treatment at baseline and year five was 2.3% and 10.3% of men with a clinical fracture. At year five, 90% of men with a fracture were untreated. Hip fractures were the most commonly treated (37.5% by year five). A diagnosis of osteoporosis resulted in greater treatment: 67% of participants with diagnosed osteoporosis were treated with a bisphosphonate and 87% were taking calcium and/or vitamin D (year five). Osteoporos Int 2008;19:581-7

Osteoporosis in the male

Lovely design in this study by Sanyal et al who suppressed sex hormones in 59 men using a GnRH agonist and aromatase blockade and then randomized to sex steroid deficiency (-T, -E), E alone (-T, +E), T alone (+T, -E), or both (+T, +E). Serum CTX and TRACP5b increased in the -T, -E despite suppression of FSH. E (not T) prevented increases in serum CTX and TRACP. E suppresses RANKL mRNA in marrow osteoblasts. E suppresses resorption more than T and increased bone resorption after sex steroid deficiency occur independently of FSH. E effects may be mediated by regulation of RANKL production by osteoblastic cells. J Bone Miner Res 2008;23:705-14

Reim et al gonadectomized 13-mo-old male Fischer-344 rats. 9-mo-old ORX rats were supplemented with testosterone undecanoate. Androgen deficiency induced a sustained decrease in periosteal bone formation. The major mechanism for cortical bone loss was an expansion of the marrow cavity with increase in endocortical eroded perimeter followed by a sustained increase in endocortical bone formation. All these changes were prevented by testosterone in an insulin-like growth factor system-independent fashion. J Bone Miner Res 2008;23:694-704

 

Note from the Editor

The purpose of Progress in Osteoporosis is to provide the reader with a summary of the most important literature published in the preceding three to four months in the field of osteoporosis. Most reviews and original research are cited. In addition, summaries and figures are provided for readers who may not have easy access to all the specialist literature. The summaries are based on the contents of abstracts, which have been abbreviated to concisely convey the main theme. The contents of the abstracts and figures should be used only as a means of directing the reader to the original literature and should not be quoted verbatim or cited as a reference. The opinions expressed in the Overview are my own and do not necessarily reflect those of the International Osteoporosis Foundation.