Overview, Vol 13, Issue 3

Only doubt is certain and disbelief worth believing.
Without this courage there can be no learning.
Believe nothing.

"The quarterly journal Progress in Osteoporosis began in October 1993 as Advances in Osteoporosis. Its purpose was to provide readers without easy access to the literature with summaries of the most important literature. We now inhabit a virtual world. Information is instantaneously accessible to all at the tap of a keyboard; understanding is not. In the spirit captured by the anonymous author*, the purpose of this publication is to provide critical evaluation of the most important literature and so to provoke discussion. It is our intention to promote dialogue which examines the quality of information published and so its credibility. The opinions expressed are my own and do not necessarily reflect those of the International Osteoporosis Foundation."

We invite readers to comment on and discuss this journal entry at the bottom of the page.

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We shall not cease from exploration
And the end of all our exploring
Will be to arrive where we started
And know the place for the first time.

T.S. Eliot
'Little Gidding', The Waste Land

Therapeutic Challenges
Are we there yet?

The contemporary history of osteoporosis began about 70 years ago with Fuller Albright reporting the common occurrence of vertebral fractures in postmenopausal women (1). Progress has been made during this short history, but there are many challenges for those blessed to continue this journey. What are these challenges?

How good are we at reducing the burden of fractures? Treatments reduce vertebral and hip fracture risk by ~50% (2). Is that ‘success’? Nonhip and nonvertebral fractures comprise about 80% of all fractures – when seeing a patient concerned about fracture risk, the likelihood is that the patient will have a nonvertebral not vertebral fracture, yet only a small number of trials demonstrate nonvertebral fracture efficacy at all.

In the few studies of antiresorptives that do demonstrate any nonvertebral antifracture efficacy based on intent to treat analyses, only risedronate, zoledronic acid, denosumab and strontium ranelate achieve this level of evidence. However, among these studies, the risk reduction is ~20%. Post hoc analysis was required to detect a benefit of alendronate against nonvertebral fractures in the Fracture Intervention Trial (FIT 1 and 2). Is this ‘success’? Why are the treatments we use producing such modest benefits? Evidence of antifracture efficacy for any drug is fragmentary among >75 year olds, women with osteopenia (the origin of 60% of fractures), men, children, and any and all drugs after 3-4 years.

What is the cure? The negative BMU balance is the cause of bone loss and structural decay (3), effectively, the cause of ‘osteoporosis’, the word so often used loosely and interchangeably with ‘fragility’. Each time a volume of bone is resorbed by the basic multicellular unit, less bone is deposited producing bone loss (4). In the presence of this negative balance, accelerated remodeling after menopause irreversibly removes bone from the intracortical, endocortical and trabecular components of the inner (endosteal) surface producing cortical porosity and thinning, trabecular thinning, perforation and loss of connectedness. By old age, half the mineralized bone volume has disappeared. Periosteal apposition continues in adulthood, but probably not after menopause, or minimally so. Each of these events – reduced formation by the BMU, increased resorption by the BMU, increased remodeling rate (more BMUs), reduced periosteal apposition – are targets for therapy.

Reducing the negative BMU balance can be achieved by reducing the volume of bone resorbed and by increasing the volume of bone formed. If BMU balance is corrected, remodeling, no matter what its intensity, will produce no permanent bone loss. Nevertheless, fragility can occur if remodeling is rapid because the excavated cavities form stress risers until they refill (5). If BMU balance is made less negative, bone loss will continue and erode the skeleton, albeit slowly, despite compliance with therapy. This continued slow loss of mineralized bone may not be detectable using bone densitometry because secondary mineralization of the larger volume of bone obscures the slow bone loss; total bone volume is decreasing, but the tissue density of the diminishing total bone volume is increasing, producing a net increase in BMD as determined using bone densitometry; this increase in bone density is not necessarily synonymous with increasing bone strength (6).

Reducing resorption depth results in smaller cortical osteons and trabecular hemiosteons with fewer lamellae, more interstitial bone (in relative and absolute terms) with higher tissue density, pentosidine collagen crosslinking and fewer osteocytes – features that may compromise material strength (7).

To restore structure, BMU balance must be made positive by increasing the volume of bone formed by the BMU. This may be achievable using exogenous PTH or treatment induced increases in endogenous PTH provided that resorption is not concurrently stimulated by PTH. This probably explains cortical bone loss occurring with ronacaleret, a calcium-sensing receptor antagonist that stimulates endogenous PTH secretion (8). This approach is probably also limited, as only ~15% of the endosteal surface is actively remodeling at any time. A more rationale target is the ~85% of the surface that is quiescent (9). About 30% of the anabolic effect of PTH is modeling based, 70% is remodeling based. The modeling effect may deposit bone upon either side of trabeculae making them thicker and more connected, upon the endocortical surface thickening the cortex and narrowing the medullary canal and upon Haversian canal surfaces reducing cortical porosity. Convincing evidence that intermittent PTH achieves all of these changes is lacking.

Completely stopping remodeling may compromise material strength (microdamage accumulation, secondary mineralization, pentosidine crosslinking), especially if baseline remodeling is low and tissue mineral density is high. If BMU balance is negative, reducing remodeling intensity is valuable as the rate of structural decay will diminish. Bisphosphonates reduce remodeling intensity by ~50% as assessed by remodeling markers, but probably not the negative BMU balance. The residual 50% remodeling with its negative BMU balance erodes bone despite treatment, particularly cortical bone (80% of the skeleton) as bisphosphonate with high matrix binding affinity does not penetrate deep cortical matrix so osteoclasts continue resorbing cortical bone (10). If BMU balance could be made positive, increasing remodeling rate would be desirable. Periosteal deposition is desirable biomechanically, but has not been convincingly demonstrated in humans

Thus, preventing and reversing bone fragility requires assessment of baseline material composition, microstructure, remodeling balance and intensity to allow reasoned choices. Single therapy may suffice in preventing structural decay. Reversing structural decay may require combined or sequential use of anabolic, antiresorptives and agents specifically designed to influence material strength. While some of these approaches have been tested, none has been designed based on abnormalities in baseline morphology, modeling and remodeling, none have fracture outcomes, and none have measured morphological changes with fracture outcomes in the same trial to then determine whether these morphological changes may serve as surrogates for fracture endpoints. The search for effective therapies and new targets is not over.

There are more things in heaven and earth, Horatio
Than are dreamt of in your philosophy.

W. Shakespeare
Hamlet (Act 1, scene 5)

Osteoclasts Regulate Bone Formation

Lotinun et al have published a real knockout (KO) (11). There are many lessons. If you think the clotting pathway is complicated, put on your safety belt and helmet. It is well appreciated now that osteoblast precursors produce RANKL which binds to its receptor RANK on osteoclast precursors facilitating differentiation into mature bone resorbing osteoclasts. What is less well appreciated is that osteoclasts participate in osteoblastogenesis and bone formation.

Cathepsin K is secreted by osteoclasts and degrades collagen during bone resorption. Global deletion of the gene encoding cathepsin (Ctsk) in mice decreases bone resorption producing more shallow resorption pits ex vitro. However, this KO is also associated with increases bone formation rate suggesting KO of this gene facilitates production of a factor or factors that facilitate bone formation.

The authors generated osteoclast-targeted Ctsk KO mice. This resulted in increased bone volume and BFR, increased osteoclast and osteoblast numbers. MicroCT showed an increase in femur cancellous bone volume, trabecular number, and connectivity density, with a concomitant decrease in trabecular separation. Deletion of Ctsk in osteoclasts also led to an increase in femoral total and cortical cross­sectional area with no change in medullary area implying an increase in periosteal bone formation; a reasonable inference but not directed demonstrated using dynamic histomorphometry. (Deletion of Ctsk in osteoblasts did not affect bone resorption or BFR.)

It gets more interesting. What are the factors produced by osteoclasts that may contribute to bone formation when this gene is knocked out? Sphingosine kinase 1 (Sphk1) catalyzes the phosphorylation of sphingosine to sphingosine­1­phosphate (S1P), which promotes osteoblast differentiation and bone forming activity (12). Deletion of Ctsk in osteoclasts increases sphingosine kinase 1 (Sphk1) expression. Conditioned media from Ctsk-deficient osteoclasts contained elevated levels of S1P, increased alkaline phosphatase and mineralized nodules in osteoblast cultures. An S1P1,3 receptor antagonist inhibited these responses. Osteoblasts from mice with Ctsk-deficient osteoclasts had an increased RANKL/OPG ratio that increased osteoclast numbers.

Thus, cathepsin K inhibits expression the gene Sphk1 regulating synthesis of S1P. The authors infer that deletion of CTSK in osteoclasts enhances bone formation in vivo by increasing the generation of osteoclast-derived S1P. Thus, S1P appears to be a ‘coupling’ factor produced by osteoclasts, perhaps one of many. This paper is well worth reading, as is reference 12 cited here and referred to in the paper. I thank the authors for educating me.

Adhere and You Will be OK
But not necessarily because of what you adhere to

Medication adherence may be a surrogate for healthy behaviors and better outcomes. Several studies report that adherence to placebo leads to better outcomes than poor adherence to placebo. This is an important observation for several reasons. Curtis et al report that in 13,444 postmenopausal women observed for 106,066 person-years, high placebo adherence was associated with hip fracture [hazard ratio (HR), 0.50; 0.33-0.78], myocardial infarction (HR, 0.69; 95% CI 0.50-0.95), cancer death (HR, 0.60; 95% CI 0.43-0.82), and all-cause mortality (HR, 0.64; 95% CI 0.51-0.80) after adjustment for potential confounders (13). Women with low adherence to placebo were 20% more likely to have low adherence to statins and osteoporosis medications. This is a fascinating observation. Studies of drug trials in which compliance is poor often report subanalyses of adherers, and when there is an association with a better outcome the investigators infer the lower event rate is evidence of efficacy of the treatment. This is common in the study of calcium and vitamin D supplementation trials where failure of compliance is common.

Tibolone and Breast Cancer

Bundred et al report that in LIBERATE, a randomized, placebo-controlled, double-blind trial, tibolone (Livial) treatment was associated with increased risk of breast cancer recurrence; HR 1.40 (95% CI 1.14-1.70; P=0.001) (14). Women with surgically excised primary breast cancer within the last 5 years were assigned to tibolone, 2.5 mg daily, or placebo for 5 years. The BMD substudy evaluated 699 women. Women with normal BMD had increased breast cancer recurrence with tibolone, 22 (15.6%) of 141 compared with placebo, 11 (6.9%) of 159 (P=0.016), whereas no increased breast cancer recurrence was seen in women with low BMD; 15 (7.4%) of 204 taking tibolone vs. 13 (6.7%) of 195 taking placebo.

TSH and Bone Loss

Thyroid stimulating hormone receptor (Tshr) KO mice are osteopenic. To determine whether low TSH contributes to bone loss in hyperthyroidism, Baliram et al compared the wildtype (WT) and Tshr KO mice rendered hyperthyroid (implanted with T4 pellets) (15). Hyperthyroid mice lacking TSHR had greater bone loss than hyperthyroid WT mice suggesting that absence of TSH signaling contributes to bone loss.

Sympathetic Nervous System and Bone Loss

Farr et al report that in rodents, sympathetic activity reduces bone formation mediated by osteopontin (16). Sympathetic activity was assessed by microneurography at the peroneal nerve in 23 women aged 20-72 years (10 pre- and 13 postmenopausal). Sympathetic activity (bursts per 100 heart beats) was 2.4-fold higher in post- than premenopausal women. In the groups combined, sympathetic activity correlated inversely with trabecular bone volume fraction (r=-0.55, P<0.01) and thickness (r=-0.59, P<0.01), and with P1NP in postmenopausal women (r=-0.65, P=0.015), with a trend in premenopausal women (r=-0.58, P=0.082). Sympathetic activity negatively correlated with plasma osteopontin (r=-0.43, P=0.045), driven mainly by the correlation in postmenopausal women (r=-0.76, P=0.002).

Age at Menarche and Fracture Risk

Delayed menarche may associate with continued skeletal growth due to failure close the epiphyseal plates. In addition, there may be a reduction in cortical thickness due to reduced endocortical apposition which in turn may produce a larger medullary canal and lower areal BMD and total vBMD. The authors produce the first quantitative assessment of bone microstructure associated with later menarche.

Chevalley et al quantified the fracture risk and late menarcheal age (MENA) in 124 healthy girls between 7.9-20.4 years of age. Sixty-one fractures occurred in 42 subjects (17). At 20.4 years, subjects with fractures had lower radial diaphysis and metaphysis aBMD, lower distal radius trabecular vBMD and thickness, and reduced stiffness, failure load, and apparent modulus. OR for a 1-SD reduction in radial aBMD diaphysis 1.97 and metaphysis 1.97 and distal radius trabecular vBMD 1.89, thickness 1.97, stiffness 2.02, failure load 2.00, and apparent modulus 1.79. MENA occurred at a later age in subjects with fractures. For MENA 1 SD (1.2 yr) later, the increase of fracture risk was 2.1 (P=0.002). Low trabecular vBMD and thickness in the distal radius are associated with reduced bone strength and increased fracture risk during growth.

Accelerated Bone Loss in Men is an Independent Risk Factor for Nonspine Fractures

Bone fragility in men remains a neglected area of research and nonspine fractures remain the most common fracture in the community. Cawthorn et al assessed the role of bone loss as an independent risk factor for fracture (18). High remodeling may produce bone fragility by producing stress risers; excavated cavities concentrate stress and predispose to microcracking.

BMD was assessed during 4.6 years for 4470 men aged ≥65 years in MrOS. BMD change was ‘accelerated’ (≤-0.034 g/cm2), ‘expected’ (0 and -0.034 g/cm2), or ‘maintained’ (≥). 371 (8.3%) men experienced at least one nonspine fracture, 78 (1.7%) hip fractures. Men with accelerated femoral neck BMD loss had an increased risk of nonspine fracture HR=2.0; 95% 1.4-2.8; nonspine/nonhip fracture HR=1.6; 95% CI 1.1-2.3; and hip fracture HR=6.3; 95% CI 2.7-14.8 compared with men who maintained BMD. Adjustment for the final BMD attenuated the risk relationship between rates of loss and fracture. Accelerated bone loss is an independent risk factor for hip and other nonspine fractures in men.

There is More than One Way to Form Bone with Leptin

It is held that, at least in mice, leptin, acts through a hypothalamic relay to decrease bone formation. Turner et al report that leptin acts through peripheral pathways to increase osteoblast number and activity (19). Leptin receptor-deficient db/db, leptin-deficient ob/ob, and ob/ob mice were treated with leptin and had hypothalamic leptin gene therapy. Decreases in bone growth, osteoblast-perimeter and bone formation rate were observed in ob/ob mice and increased in ob/ob mice following subcutaneous leptin. Hypothalamic leptin gene therapy increased osteoblast-perimeter in ob/ob mice. In spite of normal osteoclast-lined bone perimeter, db/db mice exhibited a mild generalized osteopetrotic-like phenotype and reduced turnover markers. WT mice engrafted with db/db bone marrow (BM) are not capable of directly responding to leptin and did not differ in energy homeostasis from untreated WT mice or WT mice engrafted with WT BM, indicating that central leptin signaling was not disturbed by BM transplant. Bone formation in WT mice engrafted with WT BM did not differ from WT mice, whereas bone formation in WT mice engrafted with db/db cells did not differ from the low rates observed in untreated db/db mice, indicating that leptin acting peripherally increases bone mass.

The Achilles’ Heel of the Femoral Neck

The superior cortex of the femoral neck is thin and liable to undergo more rapid bone loss (20). Milovanovic et al extend these observations to suggest that trabecular morphology in this region is also severely compromised (21). The investigators analyzed the trabecular bone microarchitecture in the inferomedial and superolateral subregions of the femoral neck in 29 Caucasian female cadavers (15 with hip fracture: age 79.5 years; and 14 without hip fractures: age 74.1 years). The fracture group had lower bone volume fraction (6.3 vs. 11.2%), connectivity density (0.33 vs. 0.74/mm3) and higher separation (0.87 vs. 0.83 mm). The superolateral neck had greater deficits in most parameters in the fracture group; lower trabecular bone volume fraction (3.6 vs. 8.2%), connectivity (0.21 vs. 0.63/mm3), more rod like trabeculae (SMI: 2.94 vs. 2.62), higher separation and the thinned trabeculae (Tb.Sp: 0.89 vs. 0.85 mm; Tb.Th: 0.17 vs. 0.20 mm).

Figure 1. Comparison of microarchitectural parameters between the fracture and nonfracture (control) group for the superolateral and inferomedial neck: bone volume fraction (BV/TV), connectivity density (Conn.D), structural model index (SMI), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular separation (Tb.Sp), degree of anisotropy (DA). Bars indicate SE. (*p≤0.05, **p≤0.01, ***p≤0.001). Reproduced from Bone, 50:63-8, Copyright (2012), with permission from Elsevier.

Regional Variation in Cortical Porosity

Kazakia et al characterized the spatial variability in cortical geometry and microstructure using HR-pQCT scans of 92 females and 54 males, 20-78 years (22). Cortical porosity (Ct.Po) displayed the greatest regional variations. Differences in Ct.Po were most pronounced in the anterior quadrant of the radius (36% lower in women) and the posterior quadrant of the tibia (27% lower in women). Comparing elderly to young women, differences in Ct.Po were most pronounced in the lateral quadrant of the radius (328% higher in elderly women) and the anterior quadrant of the tibia (433% higher in elderly women). Comparing elderly to young men, the most pronounced age differences were found in the anterior radius (205% higher in elderly men) and the anterior tibia (190% higher in elderly men). All subregional Ct.Po differences provided greater sensitivity to gender and age effects than those based on the global means. Regional analysis may be important in studies of disease and therapeutic effects.

Figure 2. Upper: The mean percent difference from the global mean in cortical indices in each subregion in the distal radius (N=140, top) and tibia (N=145, bottom). Significant regional variation was detected in cortical porosity (Ct.Po), mean pore diameter (Ct.Po.Dm), heterogeneity of pore diameter (Ct.Po.Dm.SD), and cortical thickness (Ct.Th). Significant differences from global mean ap<0.05, bp<0.01, cp<0.001. Lower: Changes in Ct.Po with age for males (right) and females (left) globally (blue) and in the anterior quadrant of the radius (red). Women show comparable increases across quadrants in porosity as they age. Men also show comparable change across quadrants, except in the anterior radius, where porosity accelerates with age relative to other quadrants. Error bars = 1 SD from the mean. Reproduced from Bone, 52:623-31, Copyright (2013), with permission from Elsevier.

Micromechanical Properties and Ibandronate Independent of Tissue Mineral Density

Bala et al analysed 110 iliac biopsies from patients treated for 22 or 34 months with placebo (n=36), 2.5 mg daily oral ibandronate (n=40), or 20 mg intermittent oral ibandronate (n=34) (23). The annual cumulative exposures were about half the therapeutic doses licensed for postmenopausal osteoporosis women. Degree of mineralization of bone (DMB) and its distribution did not differ from placebo. Hardness (Hv) was higher in the cortical, cancellous, and total bone, but DMB and Hv, measured in 3760 bone structural units, correlated (r=0.59-0.65, p<0.0001). The authors infer that a low annual cumulative exposure of ibandronate altered the bone micromechanical properties irrespective of changes in secondary mineralization. The reasons for the increase in hardness remain unknown.

Burden of Hip Fractures in Osteoporosis

Oden et al assessed the number of hip fractures for 2010 and the proportion attributable to osteoporosis (24). The total number of new hip fractures for 58 countries was 2.32 million (741,005 in men, 1,578,809 in women). Of these, 1,159,727 (50%) would be saved if BMD in individuals with osteoporosis were set at a T-score of -2.5 SD. The majority (83%) of these ‘prevented’ hip fractures were found in men and women at the age of ≥70 years. The 58 countries assessed accounted for 83.5% of the world population aged ≥50 years. Extrapolation to the world population using age- and sex-specific rates gave an estimated number of hip fractures of about 2.7 million in 2010, of which 1,364,717 were preventable by avoiding osteoporosis (264,162 in men, 1,100,555 in women). Osteoporosis accounts for about half of all hip fractures.

The Second Hip Fracture

Omsland et al studied all hip fractures in Norwegian hospitals during 1999-2008 (25). Among the 81,867 persons who sustained a first hip fracture, 6161 women and 1782 men suffered a second. Risk was no different by sex; but after taking competing risk of death into account, the age-adjusted HR of a second hip fracture was 1.40 (95% CI 1.33-1.47) in women compared to men. The greater risk in women was due to a higher mortality in men. The authors estimate that 15% of women and 11% of men will have suffered a second hip fracture within 10 years of the first.


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Bisphosphonate therapy for osteoporosis: benefits, risks, and drug holiday
McClung M, Harris ST, Miller PD, Bauer DC, Davison KS, Dian L, Hanley DA, Kendler DL, Yuen CK, Lewiecki EM
Am J Med 2013;126:13

Menopausal hormone therapy for the primary prevention of chronic conditions: U.S. Preventive Services Task Force recommendation statement
Moyer VA; U.S. Preventive Services Task Force
Ann Intern Med 2013;158:47

WNT signaling in bone homeostasis and disease: from human mutations to treatments
Baron R, Kneissel M
Nat Med 2013;19:179

Molecular mechanisms of vitamin D action
Haussler MR, Whitfield GK, Kaneko I, Haussler CA, Hsieh D, Hsieh JC, Jurutka PW
Calcif Tissue Int 2013;92:77

Physiological insights from the vitamin d receptor knockout mouse
Demay MB
Calcif Tissue Int 2013;92:99

Genetic regulation of vitamin D levels
Dastani Z, Li R, Richards B
Calcif Tissue Int 2013;92:106

What is the optimal dietary intake of vitamin D for reducing fracture risk?
Dawson-Hughes B
Calcif Tissue Int 2013;92:184

Is high dose vitamin D harmful?
Sanders KM, Nicholson GC, Ebeling PR
Calcif Tissue Int 2013;92:191

Prevention and treatment of vitamin D deficiency
Sinha A, Cheetham TD, Pearce SH
Calcif Tissue Int 2013;92:207

What is vitamin D insufficiency? And does it matter?
Heaney RP
Calcif Tissue Int 2013;92:177

Contributions of sunlight and diet to vitamin D status
Macdonald HM
Calcif Tissue Int 2013;92:163

Vitamin D and its role in skeletal muscle
Ceglia L, Harris SS
Calcif Tissue Int 2013;92:151

Vitamin D and pregnancy: skeletal effects, nonskeletal effects, and birth outcomes
Hollis BW, Wagner CL
Calcif Tissue Int 2013;92:128

Vitamin D assays: past and present debates, difficulties, and developments
Fraser WD, Milan AM
Calcif Tissue Int 2013;92:118

Bone complications of mastocytosis: a link between clinical and biological characteristics
Guillaume N, Desoutter J, Chandesris O, Merlusca L, Henry I, Georgin-Lavialle S, Barete S, Hirsch I, Bouredji D, Royer B, Gruson B, Lok C, Sevestre H, Mentaverri R, Brazier M, Meynier J, Hermine O, Marolleau JP, Kamel S, Damaj G
Am J Med 2013;126:75.e1

What are the effects of leptin on bone and where are they exerted?
Idelevich A, Sato K, Baron R
J Bone Miner Res 2013;29:18

Beyond gap junctions: Connexin43 and bone cell signaling
Plotkin LI, Bellido T
Bone 2013;52:157