Overview, Vol 13, Issue 6

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

"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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Combined Therapy in Osteoporosis
Don’t dismiss this option

Combining an anabolic agent like PTH with an antiresorptive makes sense, but initial studies combining PTH with alendronate reported blunting of the effect on bone density and remodeling markers (1). Not all studies reported blunting. Some as the combination of PTH and zoledronic acid reported a greater BMD response than either drug alone, while others reviewed below report comparable effects of combined and single therapy.

Despite the (i) inconsistent observations, (ii) lack of evidence that changes in BMD or remodeling markers are sensitive and specific markers of antifracture efficacy, and (iii) lack of data concerning morphology or antifracture efficacy, the perception in the scientific community is that combined therapy as not useful in fracture prevention. This is a regrettable situation given there are limited options available for patients who cannot tolerate bisphosphonates or patients who sustain fractures despite compliance with bisphosphonates.

The assumption that a lesser effect of combined therapy on BMD reflects a less antifracture efficacy is not evidence based. The main determinant of a rise in BMD following bisphosphonate therapy is baseline remodeling rate. The more rapid the baseline remodeling rate, the greater the BMD response to the same dose of bisphosphonate or other antiresorptive agent. The net increase in BMD is due to the following: (i) a reduction in porosity as cortical pores and trenches upon trabeculae excavated prior treatment refill – the higher the remodeling rate, the greater the number of excavated pores and resorption pits upon trabecular surfaces that will refill when an antiresorptive is administered. (ii) The appearance of fewer resorption cavities – denosumab virtually eliminates the birth of new cavities, alendronate reduces these by about 50-60%, zoledronic acid by 90% in the first month then similar to alendronate based on suppression of remodeling markers. (iii) Secondary mineralization of the bone matrix that is not resorbed (because remodeling rate is reduced) and more complete mineralization of osteons formed months earlier as secondary mineralization takes many months to complete. The net effect of reduced porosity is likely to reduce bone fragility. The secondary mineralization is the dominant mechanism of the increase in BMD after about 12 months and this may be beneficial or deleterious depending on the pretreatment tissue density; if initially high, further increases may compromise the toughness of the material; its ductility may diminish.

What happens with PTH? The anabolic effect of PTH has two components, a remodeling dependent effect said to account for over 70% of the anabolic effect and a modelling based effect accounting for the remaining 30% of the anabolic effect. When administered alone, the rise in P1NP and increase in BMD may be a consequence of either or both. The rise in BMD may underestimate the increase in bone matrix volume in either situation because newly deposited bone by direct periosteal, intracortical, endocortical or trabecular bone formation may initially deposit bone of low tissue density resulting in a net under estimate in rise in net BMD or even misleadingly produce a fall in BMD. The same may occur when PTH stimulates bone formation within remodeling sites; the newly deposited bone may be undermineralized initially. If PTH replaces older more mineralized bone with a larger volume of new bone, BMD may fall again, misleadingly suggesting there this bone loss when in fact bone matrix volume increases; quite a misleading as deposition of new bone upon the periosteum or upon trabeculae is likely to be of benefit to bone strength.

There have been no studies examining the antifracture efficacy of combined or sequential therapy using antiresorptives and anabolic agents and no studies examining the effect on bone microarchitecture. The lack of data leaves only BMD and remodeling markers as the outcome variables and this is a serious problem because neither can be relied upon as valid surrogates of antifracture efficacy. There is a lot at stake. The below papers should be viewed in this light.

In a study by Yang et al, 3 month old female rats were divided into sham or ovariectomy (OVX, PTH, IBN and COM). Weekly low-dose PTH and/or ibandronate or vehicle were administered (2). PTH, ibandronate or its concurrent treatment reversed ovariectomy induced deterioration in trabecular and cortical bone. PTH plus ibandronate preserved BMD and increased periosteal formation and a decreased endocortical resorption.

Muschitz et al reported coadministration of raloxifene or alendronate following 9 months of teriparatide in 125 postmenopausal women (3). Open-label alendronate (70 mg/week), raloxifene (60 mg/d) or no medication were given in addition to continued teriparatide (18). P1NP did not change during teriparatide monotherapy and decreased with alendronate and raloxifene; CTX did not change with teriparatide monotherapy, decreased in the alendronate group and remained elevated in the raloxifene group. The increase in spine BMD was 5% in the alendronate and 6% in the raloxifene combination groups compared with 2.8% in the teriparatide monotherapy group. The increase of spine BMD for alendronate and raloxifene groups was superior to teriparatide monotherapy. Total hip BMD changes were 4% for the alendronate combination group and 1.4% for the teriparatide monotherapy, and 1.4% for the raloxifene combination group. With the exception of no differences in the trabecular compartment of femoral neck, volumetric BMD changes in the alendronate combination group for all other comparisons were superior to the two other groups. The authors infer alendronate added to teriparatide results in a more robust increase in BMD.

Tsai et al enrolled postmenopausal women with osteoporosis to receive 20 μg TPTD daily, 60 mg denosumab every 6 months, or both during 12 months (4). Spine BMD increased more in the combination group 9.1% than in the teriparatide (6.2%) or denosumab groups. Femoral neck BMD also increased more in the combination group (4.2%) than in the teriparatide (0.8%) and denosumab (2.1%) groups, as did total hip BMD (combination, 4.9%; teriparatide, 0.7%; denosumab, 2.5%). The authors infer combination treatment might be useful to treat patients at high risk of fracture. Note that a large proportion of the subjects has previous bisphosphonate therapy. While the authors say the results were no different excluding these subjects, the data was not shown and residual effects on increments in BMD and prolonged suppression of remodeling may influence percent changes in these traits.

Schafer et al reported that postmenopausal women with low bone mass (n=43) were treated with 6 months of PTH(1-84) (100 µg/day), either as one 6- or two 3-month courses, with ibandronate (150 mg/month) during 2 years (5). Changes in HR-pQCT parameters did not differ between treatments. The groups were pooled. Trabecular BMD increased at radius and tibia. Cortical thickness and BMD decreased at the radius but did not change at the tibia. Cortical porosity increased at the tibia, not radius. Stiffness and failure load decreased at the radius but did not change at the tibia. The authors infer cortical and trabecular changes in response to the PTH/ibandronate were different at the nonweight-bearing radius vs. the weight-bearing tibia, with more favorable overall changes at the tibia. They suggest that weight bearing may optimize the effects of osteoporosis therapy. If these measurements are correct then how is antifracture efficacy achieved?


Do We Need Randomized Comparator Trials?

Lindsay et al reported a comparison between the anti-hip fracture efficacy of alendronate and risedronate (6). While it is tradition to compare treatments in a randomized controlled comparator trial, the authors took a rather different approach in a post hoc analysis comparing the results with a ‘control’ group of patients filling a single bisphosphonate prescription only and thereby assuming this was a no treatment group. In previous trials there was a suggestion of an earlier reduction in fracture rates with risedronate than alendronate, perhaps because of the lower binding affinity or risedronate to mineral allowing this drug to penetrate more deeply into cortical bone than ALN and thereby accessing and inhibiting intracortical remodeling sooner or more effectively than alendronate. The authors observed three cohorts of women who initiated once-a-week dosing of bisphosphonate; (1) patients adherent to alendronate (n=21,615), (2) patients adherent to risedronate (n=12,215), or (3) patients filling only a single bisphosphonate prescription (n=5390) as a referent population. In this cohort, the authors reported that at 12 months a significant reduction of hip and nonvertebral fractures with risedronate but not with alendronate. At the end of 2 years, the cumulative incidence of hip fractures in the referent cohort was 1.9%, and incidence of nonvertebral fractures was 6.3%. Relative to the referent, 6 months after initiating therapy and continuing through 2 years, both risedronate and alendronate cohorts had approximately a 45% lower incidence of hip fractures and a 30% lower incidence of nonvertebral fractures. The authors infer that both risedronate and alendronate reduce the risk of hip and nonvertebral fracture after two years of treatment with an earlier effect of risedronate. Ultimately, the test needed remains a randomized comparator trial as factors other than the therapy influencing fracture outcomes, whether known or unknown, can only be assumed to be equally distributed in the two groups when participants are randomly allocated to therapy and compliance is monitored. If this principle is ignored the veracity of the scientific method is in question.


Bisphosphonate-related Osteonecrosis of the Jaw (BRONJ)

Mozzati et al reported 700 consecutive patients treated with oral bisphosphonates who underwent 1480 extractions: 864 in the mandible and 616 in the maxilla (7). 334 were treated with delicate surgery and closure by primary intention and 366 were treated with nontraumatic avulsion and closure by secondary intention. No intraoperative complications were observed, and there was no evidence of postoperative bisphosphonate-associated osteonecrosis of the jaw.


Atypical Subtrochanteric Fractures

Atypical femur fractures (AFFs) located in the subtrochanteric region and diaphysis of the femur have been reported in patients taking bisphosphonates, and in patients on denosumab, but also occur in patients with no exposure to these drugs. In this report, Shane et al reviewed studies on the epidemiology, pathogenesis and medical management of AFFs published since 2010 (8). AFFs are stress or insufficiency fractures. The original definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution. The periosteal stress reaction at the fracture site was changed from a minor to a major feature. The association with specific diseases and drug exposures was removed from the minor features. Studies with radiographic review consistently report associations between AFFs and bisphosphonate use, although the strength of associations and magnitude of effect vary. Although the relative risk of patients with AFFs taking bisphosphonates is high, the absolute risk of AFFs is low, 3.2-50 cases per 100,000 person-years. However, long-term use may be associated with higher risk (approximately 100 per 100,000 person-years). Bisphosphonates localize in areas that are developing stress fractures; suppression of targeted intracortical remodeling at the site of an AFF could impair healing. When bisphosphonates are stopped, risk of an AFF may decline. Lower limb geometry and Asian ethnicity may contribute to the risk of AFFs. There is inconsistent evidence that teriparatide may advance healing of AFFs.

Schilcher et al reported that in a previous nationwide study in Sweden, 59 atypical and 218 ordinary fractures were diagnosed (9). The fracture angle (0-180°) was measured. Presence of local lateral cortical thickening (a callus reaction), more than two fragments, or a medial spike was noted. Frequency distribution analysis of the fracture angle showed 57 (25%) of 277 fractures with a mean of 89° and SD of 10°. Forty-two of 57 patients used bisphosphonates, whereas 27 of 213 others did (specificity 0.93; 95% CI 0.88-0.96). Presence of a callus reaction had also a high specificity for bisphosphonate use (0.96; 95% CI 0.92-0.98). The ASBMR criteria had a lower specificity, increasing the number of atypical fractures without bisphosphonate use from 13 to 31. This led to a decrease in age-adjusted relative risk associated with bisphosphonate use from 47 (95% CI 26-87) to 19 (95% CI 12-29). Differences in diagnostic criteria may partially explain the large differences in relative risk between different population-based studies.

From August 2009 to March 2011, Allison et al reported 220 femoral radiographs in 110 asymptomatic patients (101 women, 9 men, age 47-94) were reviewed by two radiologists (10). All patients received bisphosphonate for at least 3 years and had no history of hip/thigh pain. MRI was performed when a fracture was suspected on radiographs. Two of 110 patients (1.82%, CI 0.6-6.3%) had 3 incomplete fractures. Both patients, age 50 and 57, were Caucasian, active and on bisphosphonate for 8 years. MRI confirmed radiographic findings in both patients. Both women had T-scores in the osteopenic range at two sites and osteoporotic range at one site. The 1.82% frequency of incomplete fractures in asymptomatic patients on long-term bisphosphonate therapy is higher than that suggested in the literature. Statistical differences between fracture and nonfracture groups were not presented as the patient population was too small to draw any significant conclusions.


Bisphosphonates and Protection against
Myocardial Infarction

Bisphosphonates have been reported to be associated with reduce mortality in patients with osteoporotic fractures. Wolfe et al sought to determine if bisphosphonate use is associated with a reduced risk of myocardial infarction (MI) in 19,281 patients with rheumatoid arthritis (11). Among 5689 patients treated with bisphosphonates, the risk of MI while treated with bisphosphonate compared to when not treated was 0.56 (95% CI 0.37-0.86; p<0.01). In models including all 19,281 treated and untreated patients, the adjusted risk of first MI was 0.72 (95% CI 0.54-0.96; p=0.02) and of all MIs it was 0.72 (95% CI 0.53-0.97; p=0.03) in bisphosphonate users compared to nonusers.


Poor Compliance and Fractures

Olsen et al reported a national dataset was extracted with all treatment-naive patients who began oral bisphosphonate treatment for osteoporosis in Denmark between 1997-2006 (N=54,876, 87% women) (12). Patients who survived for at least two years (N=47,176) were divided into groups based on medication possession ratio (MPR). For alendronate, the adjusted risk of major osteoporotic fractures was reduced (OR 0.768; 0.686-0.859), including fractures of the hip (0.718; 0.609-0.846) and humerus (0.54; 0.431-0.677) with MPR ≥0.8. The risk reduction was lower with etidronate. Over two years, 171 hip fractures and 53 other major osteoporotic fractures were attributed to suboptimal or poor refill compliance, with an excess cost of 13.7 M DKK (2.5 M USD).


Undercarboxylated Osteocalcin and Testosterone

In animal studies, undercarboxylated osteocalcin (ucOC) is reported to be important for male fertility and testosterone production by testes. Kanazawa et al reported ucOC is positively associated with free testosterone in 69 men with type 2 diabetes (13). ucOC and ucOC/total OC (TOC) ratio were associated with free testosterone and negatively with LH (for ucOC, β=0.30, p=0.042 and β=-0.52, p=0.048; for ucOC/TOC ratio, β=0.31, p=0.031 and β=-0.54, p=0.036, respectively) independent of age, duration of diabetes, BMI, and hemoglobin A1c.

Bisphosphonates reduce osteocalcin levels. Bolland et al determined whether reductions in osteocalcin induced by zoledronic acid impact negatively on testosterone levels in 43 HIV-infected men treated for two years using annual 4 mg zoledronic acid (14). Serum testosterone was measured at baseline, 3 months, and 2 years; luteinizing hormone at 3 months and 2 years; and total osteocalcin at 2 years in 28 participants. At 2 years, total osteocalcin was 39% lower in the zoledronic acid group than the placebo (zoledronic acid mean 10.1 [SD 3.0] µg/L, placebo 16.5 [SD 4.9] µg/L, P=0.003). Testosterone levels did not change over time in either group and there were no between-group differences over time, P=0.4 (mean change at 2 years [adjusted for baseline levels] in zoledronic acid group -0.4 nmol/L, 95 % CI -2.5 to 1.6; placebo group 0.4 nmol/L, 95 % CI -1.6 to 2.5).


Lactation
A fascinating model of uncoupling

Collins et al reported that Ctcgrp (calcitonin/calcitonin gene related peptide α) null mice lose 50% of spine mineral content during lactation but restore it fully (15). Ctcgrp null mice have twice as many osteoclasts and 30-40% fewer osteoblasts compared with wild-type during lactation but no deficit in osteoblast numbers after weaning. Genomewide microarray analyses on tibial RNA showed differential expression of 729 genes in wildtype mice at day 7 after weaning vs. prepregnancy, whereas the same comparison in Ctcgrp null mice revealed only 283 genes. Downregulation of Sost and Dkk1, and inhibition of Mef2c, a sclerostin stimulator, was observed. Ctsk, a gene expressed during osteoclast differentiation, and Igfbp2, which stimulates bone resorption, were inhibited. Differential regulation of genes involved in energy use was compatible with a net increase in bone formation. The most marked changes occurred in genes not previously associated with bone metabolism. The postlactation skeleton shows dynamic activity with more than 700 genes expressed. Some promote bone formation during postweaning by stimulating the proliferation and activity of osteoblasts, inhibiting osteoclasts, and increasing energy use.


References

1. Seeman E. Anabolic plus antiresorptive: Is one plus one more or less two? IBMS BoneKEy 2011;8:221 (doi:10.1138/20110510).

2. Yang X, Muthukumaran P, Dasde S, et al. Positive alterations of viscoelastic and geometric properties in ovariectomized rat femurs with concurrent administration of ibandronate and PTH. Bone 2013;52:308.

3. Muschitz C, Kocijan R, Fahrleitner-Pammer A, Lung S, Resch, H. Antiresorptives overlapping ongoing teriparatide treatment result in additional increases in bone mineral density. J Bone Miner Res 2013;28:196.

4. Tsai JN, Uihlein AV, Lee H, et al. Teriparatide and denosumab, alone or combined, in women with postmenopausal osteoporosis: the DATA study randomised trial. Lancet 2013;doi:10.1016/S0140-6736(13)60856-9.

5. Schafer AL, Burghardt AJ, Sellmeyer DE, et al. Postmenopausal women treated with combination parathyroid hormone (1-84) and ibandronate demonstrate different microstructural changes at the radius vs. tibia: the PTH and Ibandronate Combination Study (PICS). Osteoporos Int 2013;doi:10.1007/s00198-013-2349-y.

6. Lindsay R, Watts NB, Lange JL, Delmas PD, Silverman SL. Effectiveness of risedronate and alendronate on nonvertebral fractures: an observational study through 2 years of therapy. Osteoporos Int 2013;doi:10.1007/s00198-013-2332-7.

7. Mozzati M, Arata V, Gallesio G. Tooth extraction in osteoporotic patients taking oral bisphosphonates. Osteoporos Int 2013;24:1707.

8. Shane E, Ebeling PR, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: Second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2013;doi:10.1002/jbmr.1998.

9. Schilcher J, Koeppen V, Ranstam J, et al. Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls. Bone 2013;52:389.

10. Allison MB, Markman L, Rosenberg Z, et al. Atypical incomplete femoral fractures in asymptomatic patients on long-term bisphosphonate therapy. Bone 2013;55:113.

11. Wolfe F, Bolster MB, O'Connor CM, et al. Bisphosphonate use is associated with reduced risk of myocardial infarction in patients with rheumatoid arthritis. J Bone Miner Res 2013;28:984.

12. Olsen KR, Hansen C, Abrahamsen B. Association between refill compliance to oral bisphosphonate treatment, incident fractures, and health care costs-an analysis using national health databases. Osteoporos Int 2013;doi:10.1007/s00198-013-2365-y.

13. Kanazawa I, Tanaka K, Ogawa N, Yamauchi M, Yamaguchi T, Sugimoto T. Undercarboxylated osteocalcin is positively associated with free testosterone in male patients with type 2 diabetes mellitus. Osteoporos Int 2013;24:1115.

14. Bolland MJ, Grey A, Horne AM, Reid IR. Testosterone levels following decreases in serum osteocalcin. Calcif Tissue Int 2013;doi:10.1007/s00223-013-9730-x.

15. Collins JN, Kirby BJ, Woodrow JP, et al. Lactating Ctcgrp nulls lose twice the normal bone mineral content due to fewer osteoblasts and more osteoclasts, whereas bone mass is fully restored after weaning in association with up-regulation of Wnt signaling. Endocrinology 2013; 154:140