Overview, Vol 9, Issue 4

Strontium and sustained fracture risk reduction during 5 years

There is little long term antifracture data available in the literature. Indeed, veracity of claims of anti-fracture efficacy of alendronate during 10 years are difficult to evaluate because a control group randomized at the onset of the study was not available and the controls used were from the SOF study, a prospective cohort study (Bone et al, NEJM 2004;350:1189). Most other treatments that claimed to have a sustained benefit suffer from problems with attrition of the inception cohort. Reginster et al report that in 5091 postmenopausal women with osteoporosis randomized to strontium ranelate, 2714 (53%) completed the study up to 5 years. The risk of nonvertebral fracture was reduced by 15%. The risk of hip fracture was reduced by 43% and the risk of vertebral fracture was reduced by 24%. Arthritis Rheum 2008;31;58:1687-95

RANKL inhibition

Miller et al report that denosumab, a human monoclonal antibody inhibits RANKL, osteoclast formation, function, and survival, bone turnover and increased BMD. Continuous treatment increased BMD. Discontinuation was associated with a decrease in BMD within the first 12 months and retreatment increased spine BMD. This treatment appears to offer a way of regulating remodelling rate and this may be most important because bone resorption is not necessarily a bad thing (see below). Rumor has it that denosumab also now reduces fracture risk but don’t tell anyone. Bone 2008;43:222-9

PTH administration, exercise, and tunneling

Bone adapts to the loading requirements imposed on it. Loading may be a way of targeting drug therapy. Sugiyama et al report that mice given daily PTH (1-34) with unilateral loading of the tibiae and ulnae had an anabolic response to low dose PTH at trabecular bone and in the proximal and middle cortical bone treated with all doses. In the ulna, loading that did not stimulate osteogenesis was osteogenic at the distal site with 80 μg/kg/day iPTH. At both levels of loading, there were synergistic effects in cortical bone volume of the proximal tibia and distal ulna between loading and high dose iPTH from increases in endosteal and periosteal bone formation. Bone 2008;43:238-48

Miller et al report that daily human PTH(1-84) increases trabecular bone volume, number and connectivity at lumbar vertebra-3 and thoracic vertebra-10. Intratrabecular tunneling increased in PTH(1-84)-treated animals and occurred at all skeletal sites. A modest but significant increase in trabecular thickness occurred only at the iliac crest. Bone 2008;42:1175-83

McManus et al report that Fish Fugu parathyroid hormone 1 (fPth1) given to male rats increased TbBV/TV, TbTh, TbN, mineral apposition rate (MAR) and bone formation rate/bone surface (BFR/BS) with a concomitant decrease in osteoclast surface and number. OVX osteopenic rats and sham operated (SHAM) rats were injected intermittently with 500 μg/kg for 11 weeks. This dose increased TbBV/TV and TbTh in the proximal tibiae due to increased bone formation as assessed by BFR/BS and MAR with restoration of TbBV/TV to SHAM levels without any effect on bone resorption. fPth1 also increased TbBV/TV and TbTh in the vertebrae (L6) and cortical thickness in the mid-femora, thus increasing bone strength at these sites. Bone 2008;42:1164-74

Is bisphosphonate therapy safe?

Bone resorption is not necessarily a bad thing; remodelling with resorptive removal of old or damaged bone is essential to maintaining bone’s material and structural strength. Allen et al report that bisphosphonates reduce remodelling in dog rib, but no adverse effects were noted in dose said to be equivalent to those used in postmenopausal women . While reduced bone toughness is documented in vertebrae, data in the rib following 3 years bisphosphonate are not available. Doses of alendronate estimated to be five times higher than that used in postmenopausal women reduced toughness (ability to absorb energy without cracking) by 33%, but neither ultimate stress nor modulus were reduced relative to controls. There was no difference in overall microdamage accumulation among the groups. Moreover, microdamage burden may differ from region to region. Damage burden in the rib may be less than in regions loaded more greatly. The point is that it is probably unwise to dismiss the possibility that prolonged exposure to antiresorptive agents is entirely safe. Calcif Tissue Int 2008;82:354-60

Hoff et al analyzed 4019 patients treated with intravenous bisphosphonates and report 16/1338 patients with breast cancer (1.2%) and 13/548 patients with myeloma (2.4%) developed ONJ. The median dose and duration of treatment with pamidronate or zoledronic acid were higher in patients with ONJ (p<0.0001). Zoledronic acid was associated with a HR=15.01), pamidronate followed by zoledronic acid (HR=4.00), and dental extractions (HR=53.19) as risks for ONJ in breast cancer. In multiple myeloma, dental extractions (HR=9.78) and osteoporosis (HR=6.11), 13/29 patients were followed for a median of 17.1 months, lesions healed in 3 patients. J Bone Miner Res 2008;23:826-36

Hess et al report the results of a systematic review to identify cases of osteonecrosis of the jaw among patients taking bisphosphonates for an indication other than cancer. Ninety-nine cases were identified (85 osteoporosis, 10 Paget's disease, 2 with rheumatoid arthritis, 1 with diabetes, and 1 patient with maxillary fibrous dysplasia). The mean age was 69.4 years, 87.3% were female, and 83.3% were receiving oral bisphosphonates. Of the 63 patients, 88.9% had a dental procedure before the onset of osteonecrosis. Am J Med. 2008;121:475-83

Visekruna et al report three subjects experienced spontaneous or minimal trauma "chalk-stick" type metadiaphyseal femoral fractures on long term bisphosphonate after long term, combined antiremodelling therapy. All three had concomitant circumstances (endogenous estrogen) or medications (glucocorticoids, hormone replacement therapy, raloxifene). Biochemical markers of bone turnover were low or in the low premenopausal range. Double tetracycline labeled bone biopsy showed low activation frequency in one subject and limited single tetracycline label in a second consistent with severely suppressed bone turnover. J Clin Endocrinol Metab 2008 [Epub ahead of print]

Is calcium supplementation safe?

There is a notion that various supplements “can’t do any harm”. This may be a layman’s approach to disease prevention but surely cannot be condoned by a so called learned society that prides itself on decision making based on evidence. Reid et al report an increased risk for hip fracture (relative risk 1.50, 95% CI 1.06-2.12) in 5,500 women involved in trials of calcium monotherapy. While this observation is interesting and certainly provocative, the data need to be looked at critically. Most of the trials examining the effects of calcium alone or with vitamin D have serious flaws in design (most patients are not calcium or vitamin D deficient) and execution (such as large numbers lost to follow up). Thus, any interpretation benefit or harm lacks a strong evidence base. There is no substitute for design, not even statistics can save a poorly designed trial even by squeezing out a p<0.05 with huge sample sizes. As the authors conclude, “Until there are further trial results to clarify this area, the present findings suggest that reliance on high calcium intakes to reduce the risk of hip fracture in older women is not appropriate.” Osteoporos Int 2008;19:1119-23

Is calcium supplementation efficacious?

Aloia et al published a lovely paper that will be an education to any young investigator interested in understanding remodelling and how a so called antiresorptive agent ‘increases’ BMD. In this study, the authors reported no differences in the effect of calcium vs. calcium + 800 IU vitamin D3 on BMD. A transient increase in BMD was observed during the first year of study followed by a decline. This observation is consistent with the notion that remodelling cycles initiated before intervention go to completion by bone formation within each BMU increasing BMD then at a new steady state, when remodelling is slower, bone loss again occurs because the negative BMU is not corrected. Osteoporos Int 2008;19:1001-9

Is exercise safe?

Clark et al report that in 2692 children, 193 (7.2%) reported at least one fracture over two years. Children who reported daily or more episodes of vigorous physical activity had double the fracture risk compared with those children who reported less than four episodes per week (OR, 2.06) despite having higher bone mass. J Bone Miner Res 2008;23:1012-22

Vitamin D deficiency

Vitamin D deficiency is fashionable but is there more to it? Dobnig et al reported that in 22.6% of 3258 male and females due for coronary angiography died during 7.7 years. The hazards ratio was increased in those in the lower two 1,25-D quartiles compared with the highest quartile for all-cause mortality (HR, 2.08 and 1.53, respectively) and cardiovascular mortality (HR, 2.22 and 1.82, respectively). Similar results were obtained for patients in the lowest 1,25-D quartile. Arch Intern Med 2008;168:1340-9

Giovannucci et al report in a case-control study of 18,225 men aged 40-75 years free of cardiovascular disease, that during 10 years 454 developed nonfatal myocardial infarction or fatal coronary heart disease. Controls (n=900) were selected in a 2:1 ratio. Men deficient in 25(OH)D (≤15 ng/ml were at increased risk for myocardial infarction (relative risk 2.42). Arch Intern Med 2008;168:1174-80

Associations of this kind in observational cohort studies are difficult to interpret. The implication is that deficiency in vitamin D contributed to death, but it is possible that individuals who were unwell avoid sunlight and may have lower vitamin D so the association is not causal? It is not clear what proportion of the mortality was attributable to vitamin D deficiency, nor that repletion would have reduced that mortality. There are more questions than answers.

Zhu et al report that in 302 elderly women with serum 25(OH)D <60 nM receiving 1000 mg calcium citrate per day with 1000 IU vitamin D2 or placebo, increases in BMD occurred but were no different and there was no change in serum PTH. The increase in 25(OH)D had no extra effect on active fractional intestinal calcium absorption, which fell equally in both groups. J Bone Miner Res 2008;23:1343-8

Bone is a gastrointestinal organ?

To investigators interested in bone, everything in bone is for bone but that may be a blinkered approach. Bone may be more or less, depending on the perspective taken. For example, there is evidence from the Karsenty group that bone may be an endocrine organ participating in energy metabolism with uncarboxylated osteocalcin regulating insulin sensitivity and secretion. Now Niemeier et al report chylomicron remnants (CR) injected into mice were cleared by liver and bone. Uptake of CR by murine osteoblasts and hepatocytes was similar in vitro. Electron microscopy revealed CR uptake into sinusoidal endothelial cells, macrophages and osteoblasts. Injection of vitamin K(1)-enriched CR resulted in an increase in osteocalcin carboxylation in vivo while total osteocalcin remained unaffected, so osteoblasts process CR in vivo. Bone 2008;43:230-7

GAP junctions and loading

Grimston et al report that gap junctional intercellular communication mediated by connexin 43 (Cx43) plays a role in the cellular response to mechanical stimulation. Genetic deficiency of the Cx43 gene (Gja1) in mice with a conditional Gja1 ablation in osteoblasts (ColCre; Gja1−/flox), wildtype (Gja1+/flox) and heterozygotes (Gja1−/flox) were subjected to a three-point bending. Mutants had thinner cortices, larger tibial diaphysial marrow area and total CSA. These mice needed 40% more force to generate endocortical strain. In wildtype mice, loading produced double labels at the endocortical surface, whereas single labels were seen in mutants, and mineral apposition rate and bone formation rate were lower (54.8% and 50.2%, respectively) in mutants relative to wildtype. Cx43 plays a role in adaptive responses to physical stimuli. J Bone Miner Res 2008;23:879-86

Osteocytes, sclerostin knockouts, apoptotic bodies

Sugawara et al report that the elastic modulus of peripheral regions of cells was higher than in their nuclear regions. The elastic modulus of the peripheral region of osteoblasts was 12053±934 Pa, that of osteoid osteocytes was 7971±422 Pa and that of mature osteocytes was 4471±198 Pa so the level of elastic modulus of bone cells was proportional to the stage of development. The focal adhesion area of osteoblasts was higher than that of osteocytes. Bone 2008;43:19-24

Li et al generated SOST knockout mice and report increased radiodensity throughout the skeleton. Lumbar vertebrae and whole leg showed increased BMD (>50%). μCT analysis of femur showed that bone volume was increased in the trabecular and cortical compartments. Histomorphometry revealed increased osteoblast surface and no change in osteoclast surface. The bone formation rate in SOST knockout mice was increased for trabecular bone (>9-fold) at the distal femur, as well as for the endocortical and periosteal surfaces of the femur midshaft. Mechanical testing of lumbar vertebrae and femur showed that bone strength was increased. J Bone Miner Res 2008;23:860-9

Kogianni et al report that osteocyte apoptosis colocalizes with osteoclastic bone resorption. Osteocyte apoptotic bodies (OABs) from MLO-Y4 osteocyte-like cell line and primary murine osteocytes and apoptotic bodies (ABs) from primary murine osteoblasts support osteoclastogenesis in vitro and in vivo. Addition of OABs to mononuclear osteoclast precursors (OPs) in vitro resulted in the maintenance of OP cell numbers and an increase in the proportion and activity of TRACP+ cells. The osteoclastogenic capacity of OABs was independent of RANKL but dependent on the induction of TNF-α production by OP. Dying osteocytes target bone destruction through the distribution of OAB associated signals. J Bone Miner Res 2008;23:915-27

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.