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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2803
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 8 2948-2952
Copyright © 2008 by The Endocrine Society

CLINICAL CASE SEMINAR

Severely Suppressed Bone Turnover and Atypical Skeletal Fragility

Maja Visekruna, Deborah Wilson and Fergus Eoin McKiernan

Center for Bone Disease, Marshfield Clinic, Marshfield, Wisconsin 54449

Address all correspondence and requests for reprints to: Maja Visekruna, M.D., Marshfield Clinic, 1000 North Oak Avenue, Marshfield, Wisconsin 54449. E-mail: visekruna.maja{at}marshfieldclinic.org.


   Abstract
Top
 Abstract
Introduction
 Case 1
 Case 2
 Case 3
 Discussion
 References
 
Context: Since their introduction into clinical medicine, bisphosphonates have revolutionized clinical osteoporosis care. Ironically, in rare circumstances, long-term, combined anti-remodeling therapy may be associated with skeletal harm.

Evidence Acquisition: We report atypical skeletal fragility in three subjects after long-term, combined anti-remodeling therapy.

Evidence Synthesis: Three subjects experienced spontaneous or minimal-trauma chalk-stick type metadiaphyseal femoral fractures while on long-term bisphosphonate therapy. The fracture location, type, bilaterality, prodromal pain, and delayed healing were atypical for uncomplicated postmenopausal osteoporosis. All three subjects had concomitant circumstances (endogenous estrogen) or medications (glucocorticoids, hormone replacement therapy, and raloxifene) that likely suppressed bone remodeling beyond the effect of the bisphosphonate alone. Biochemical markers of bone turnover were very low or in the low premenopausal range. Double tetracycline-labeled bone biopsy showed very low activation frequency in one subject and limited single tetracycline label in a second consistent with severely suppressed bone turnover (SSBT). These three cases resemble previous descriptions of SSBT.

Conclusion: Atypical skeletal fragility may signify SSBT in the setting of long-term, combined anti-remodeling therapy. We speculate that osteoclast tolerance for pharmacological suppression may vary among individual patients and that in some cases combined anti-remodeling therapy may result in skeletal harm.


   Introduction
Top
 Abstract
 Introduction
Case 1
 Case 2
 Case 3
 Discussion
 References
 
Osteoporosis is a major public health threat for millions of Americans. The objective of osteoporosis treatment is to maintain skeletal health and prevent fragility fracture (1). Fracture risk is determined, in part, by the strength of bone. Bone strength, in turn, is the integrated sum of the material properties and amount of bone tissue, its orientation and geometry within the skeleton, and its regenerative capacity (2). Aspects of these properties can be assessed clinically by dual x-ray absorptiometry, by biochemical markers of bone turnover, and by histomorphometric analysis of double tetracycline-labeled bone. In the future, high-resolution computerized tomography and magnetic resonance imaging may provide clinically useful surrogate measures of the mechanical strength of bone. In general, bone mineral density (BMD) measured by dual x-ray absorptiometry correlates inversely with fracture risk and is currently the most practical and reliable means of predicting future fracture risk in clinical practice. There are, however, instances in which this relationship is altered. Skeletal fluorosis and osteopetrosis are two conditions in which BMD is increased, but skeletal fragility and fracture risk are also increased (3, 4, 5). Thus, the positive correlation between BMD and skeletal strength is not absolute.

The osteopetroses are a group of rare conditions marked by functional osteoclast failure and a skeletal phenotype of high BMD, atypical skeletal fragility (chalk-stick fractures), impaired fracture healing, and an inflammatory osteomyelitis of the jaw (3, 4, 5). Variable penetrance results in wide skeletal phenotypic expression. Heterozygotes of type II autosomal dominant osteopetrosis have higher BMD than unaffected individuals, yet they lack the overt skeletal phenotype of homozygotes and they do not fracture excessively (4). Osteoclast function in heterozygotes is incompletely characterized (5). Whether osteoclast response to pharmacological agents in heterozygotes differs from unaffected individuals is unknown. It seems at least plausible that potent, osteoclast-targeted anti-remodeling therapies in individuals with subclinical, intrinsic osteoclast abnormalities could result in sufficient additional osteoclast impairment that clinical bone disease could arise. In fact, iatrogenic osteopetrosis has been ascribed to aggressive bisphosphonate therapy alone (6). In this case, high BMD, rock-hard bone, modeling abnormalities, impaired fracture healing, and elevated serum acid phosphatase and CK-BB isozymes developed in a youth after prolonged, high-dose iv pamidronate therapy. There is some basis, therefore, for the concern that excessive suppression of osteoclast function might, in rare instances, induce a physiological state resembling osteopetrosis. If so, increasing BMD might, ironically, be accompanied by increased skeletal fragility.

On the other hand, there is overwhelming evidence that potent nitrogen-containing bisphosphonates such as alendronate (ALN), risedronate, and zoledronate prevent osteoporotic fracture, reduce fracture morbidity, and may even reduce postfracture mortality in appropriately selected patients (1, 7). Notwithstanding these data, concern persists that potent and prolonged suppression of bone remodeling by these agents could eventually result in skeletal harm (8). This concern has been grounded in the prolonged residence time of bisphosphonates in bone, their nonmetabolized nature, and their ability to induce irreversible functional osteoclast failure and apoptosis. Histomorphometric findings of excess microcracks, decreased anisotropy, increased secondary mineralization, severely suppressed bone turnover (SSBT), and the rare demonstration of retained cartilaginous bars has sustained these concerns (6, 8, 9, 10, 11). Recently, long-term oral ALN treatment has been associated with increased osteoclast numbers and unusual giant, probably dysfunctional osteoclast forms (12). Similar histology can be found in type II autosomal dominant osteopetrosis, in which increased osteoclast number and giant osteoclasts appear incapable of active bone resorption (3, 4, 5, 6). Conversely, these concerns have been assuaged by the finding of normal bone histology in the vast majority of patients on long-term bisphosphonate therapy in clinical trials (13, 14).

Reports of osteonecrosis of the jaw (15, 16, 17), atypical skeletal fragility, and impaired fracture healing (8, 18, 19, 20) have rekindled concern for the skeletal safety of long-term bisphosphonate therapy. Marx et al. (17) recently correlated the occurrence and severity of osteonecrosis of the jaw with the duration of oral bisphosphonate therapy and degree of serum C-telopeptide suppression. Odvina et al. (8) described spontaneous, nonspinal fractures and SSBT in nine patients after long-term ALN therapy. Most of these patients had factors in addition to ALN that contributed to the suppression of bone remodeling. Five of these nine patients had fractures of the proximal femoral shaft, and in two patients, these fractures were bilateral. Observations such as these combined with the absence of accelerated fracture risk after discontinuing long-term bisphosphonate therapy (21) provides the motivation for recommending a periodic drug holiday from these agents.

Herein we report three additional cases of atypical skeletal fragility in the setting of prolonged oral bisphosphonate therapy (Table 1Go). These three cases conform to the previous description of SSBT (8). Our purpose is neither to prove causality nor to tip the scale of therapeutic benefit against bisphosphonates. Rather, our aim is to add to existing anecdotal evidence that suggests that long-term bisphosphonate therapy, particularly when combined with other anti-remodeling agents, may in rare instances result in skeletal harm.


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  		TABLE 1. Characteristics of the three cases

 

   Case 1
Top
 Abstract
 Introduction
 Case 1
Case 2
 Case 3
 Discussion
 References
 
A 51-yr-old, premenopausal Caucasian female with steroid-dependent rheumatoid arthritis was treated with ALN between 2001 and 2006. Her lowest ever BMD T-scores were –0.5 [lumbar spine (LS)] and –2.1 [femoral neck (FN)]. She experienced atraumatic metatarsal fractures in 1998, 1999, and 2003. In May 2006, she developed the insidious onset of bilateral, lateral hip pain without antecedent trauma or overuse. A walker became necessary for ambulation. X-rays showed bilateral, lateral metadiaphyseal femoral stress fractures that were confirmed by nuclear bone scintigraphy, computerized tomography, and magnetic resonance imaging (Fig. 1Go). ALN was discontinued in August 2006 when mean FN T-score was –1.7. The 24-h urine N-telopeptide (NTX) was 12 nM bone collagen equivalent/mM collagen (19–63) and serum NTX was 5.4 nM bone collagen equivalents (6.2–19). Intact PTH was 23 pg/ml (7–53), and 25-hydroxyvitamin D (25-OHD) was 40 ng/ml (25–80). Five months after discontinuing ALN, a double tetracycline-labeled iliac crest biopsy showed only limited single tetracycline label, marked increased osteoclast number, and reduced osteoid surface, width, and volume. The patient confirmed that both courses of tetracycline were taken correctly. Mineral apposition and bone formation rates could not be calculated. Hip pain improved after 18 months of protected weight bearing.


Figure 1
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  		FIG. 1. Case 1. Bilateral, lateral femoral metadiaphyseal fractures seen by radiography (A), nuclear bone scintigraphy (B), and computerized tomography (C).

 

   Case 2
Top
 Abstract
 Introduction
 Case 1
 Case 2
Case 3
 Discussion
 References
 
A 62-yr-old, postmenopausal Caucasian female with Crohn’s disease and rheumatoid arthritis has been steroid dependent since 1990. She was treated with estrogen replacement therapy between 1991 and 2000, raloxifene between 2000 and February 2007, and ALN between 1996 and June 2006. Her lowest ever BMD T-scores were –3.6 (LS) and –1.5 (FN). She developed bilateral thigh pain without antecedent trauma or overuse in June 2006. Bilateral chalk-stick metadiaphyseal fractures were confirmed (Fig. 2Go). Mean FN T-score just before fracture was –1.3. Fractures were stabilized by intramedullary rod fixation, ALN was discontinued and teriparatide therapy initiated. Serum NTX 8 months after discontinuing ALN and while taking teriparatide was 11.4 nM bone collagen equivalent. PTH was 32 pg/ml, and 25-OHD was 48 ng/ml. Vigorous callus formation occurred while on teriparatide. Bone biopsy was not performed.


Figure 2
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  		FIG. 2. Case 2. Bilateral femoral metadiaphyseal fractures seen radiographically at presentation (A) and 4 months after intramedullary rod fixation, discontinuation of ALN, and initiation of teriparatide therapy (B).

 

   Case 3
Top
 Abstract
 Introduction
 Case 1
 Case 2
 Case 3
Discussion
 References
 
A 75-yr-old postmenopausal Caucasian female on continuous inhaled and intermittent oral steroid therapy for pulmonary indications was faithfully compliant with oral ALN therapy since 1996. Her lowest ever BMD T-scores were –4.7 (LS) and –1.6 (FN). She previously experienced high-energy fractures of both wrists and left fibula as well as low-energy fractures of ribs and at least four thoracolumbar vertebrae. In February 2006, she fell from a standing height and sustained a chalk-stick metadiaphyseal right femur fracture that required stabilization by intramedullary rod fixation. Persistent pain 1 yr later was ascribed to fracture nonunion (Fig. 3Go). In February 2007, a 24-h urine NTX was 30 nM bone collagen equivalent/mM collagen, and serum NTX was 6.9 nM bone collagen equivalent. PTH was 18 pg/ml, and 25-OHD was 32 ng/ml. T-score of the nonfractured left FN at that time was –1.2. ALN was discontinued and 5 months later, a double tetracycline-labeled iliac crest bone biopsy showed marked increase in osteoclast and osteoblast numbers but decreased osteoid surface, volume, and width. Both single and double labels were present, but activation frequency was calculated to be only 0.0167/yr (normal, 0.42 ± 0.24/yr). The patient confirmed that both courses of tetracycline were taken correctly. Teriparatide therapy was initiated 18 months after fracture. Radiographic evidence of fracture repair was still absent 22 months after the original fracture.


Figure 3
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  		FIG. 3. Case 3. Ununited right femoral metadiaphyseal fracture seen radiographically 9 months (A) and 22 months (B) after intramedullary rod fixation and discontinuation of ALN therapy.

 

   Discussion
Top
 Abstract
 Introduction
 Case 1
 Case 2
 Case 3
 Discussion
References
 
These three patients conform to the recent description of SSBT in patients taking long-term oral bisphosphonates (8). The metadiaphyseal location, chalk-stick type, and frequent bilaterality of these femoral fractures are unusual for uncomplicated postmenopausal osteoporosis. Similar to patients initially described by Odvina et al. (8) and more recently by others (18, 19, 20), two of our patients suffered prodromal pain in the region of their atraumatic fractures. Five of the nine patients described by Odvina et al. (8) had proximal femoral shaft fractures, and in two patients, these fractures were bilateral. In each of our cases, as in most of those reported by Odvina et al. (8), there were additional circumstances (endogenous estrogen) or medications (glucocorticoids, hormone replacement therapy, or raloxifene) that likely resulted in further suppression of bone turnover beyond the effect of the oral bisphosphonate alone (1, 22). Curiously, FN T-scores were relatively normal for age in our patients before fracture (–1.7 to –0.4) as they were in those with femoral shaft fractures reported by Odvina et al. (8) (–1.1 to –0.6) (8). Fracture healing was delayed or absent in two of our patients, but vigorous callus formation was seen in the third patient within months of initiating teriparatide.

Suppression of bone remodeling is the intended physiological effect of bisphosphonate therapy (1). Biochemical markers of bone turnover in all of our patients were very low or in the low premenopausal range. This has not been a consistent finding in all cases of SSBT (8). The very low activation frequency in one of our patients and the limited single tetracycline label in the other patient 5 months after discontinuing ALN suggest that suppression of bone turnover in these patients was severe. Histomorphometry in patients taking bisphosphonates typically demonstrates a 90% reduction in bone remodeling, but single or double tetracycline labeling is almost always reported (11, 13, 14, 22, 23, 24). In women taking combined oral ALN and estrogen therapy, Bone et al. (22) reported that trabecular compartment tetracycline labeling could not be found in three of 34 biopsy specimens (8.8%). Although the authors dismissed this as an occasional finding in routine biopsies, we find it noteworthy that this finding was not present in either the oral ALN alone or oral estrogen alone comparator groups (n = 50) or in other reports from large clinical trials (13, 14). Normal osteoclasts, therefore, may not have unlimited tolerance for pharmacological suppression.

We speculate that some patients have physiologically vulnerable osteoclasts (possibly asymptomatic heterozygotes for chloride channel defects or osteoclast proton pump deficiencies) and tolerate potent nitrogen-containing bisphosphonates, particularly in combination with other anti-remodeling agents, poorly (6, 8, 18, 19, 20). The coming age of personalized medicine and pharmacogenetics is predicated on the premise that genetically different individuals have unique sensitivities to different drugs. As of 2006, more that 190 million prescriptions for oral bisphosphonates have been filled worldwide (16). Understandably, incident fracture (even atypical fracture) occurring during the course of long-term bisphosphonate therapy is likely to be attributed to underlying skeletal fragility rather than to the prescribed treatment. Vigilance for atypical skeletal fragility in this setting, particularly when potent nitrogen-containing bisphosphonates are combined with other anti-remodeling agents, may result in recognition of additional cases and strengthen this association if one exists.

Our small case series has a number of weaknesses and limitations. We have no control group, and these associations may be due to chance. Biochemical markers of bone turnover and all aspects of the bone biopsy did not uniformly indicate SSBT, although both bone biopsies were performed 5 months after discontinuing ALN. Other biochemical markers of bone turnover such as osteocalcin, procollagen-I extension peptide, bone-specific alkaline phosphatase, and pyridinoline cross-links were not performed. We have no direct evidence to support the speculation that any of our patients had intrinsically vulnerable osteoclasts, chloride channel abnormalities, or proton pump defects.

When appropriately prescribed, nitrogen-containing bisphosphonates result in overwhelmingly more good than harm, and their use should continue. Nevertheless, rare clinical associations may harbor insights into normal physiology. The speculation that osteoclast tolerance for pharmacological suppression may vary among individuals should be explored. In some patients, combined anti-remodeling therapy may result in skeletal harm.


   Footnotes
 
Disclosure Statement: The authors have nothing to disclose.

First Published Online June 3, 2008

Abbreviations: ALN, Alendronate; BMD, bone mineral density; FN, femoral neck; LS, lumbar spine; NTX, N-telopeptide; 25-OHD, 25-hydroxyvitamin D; SSBT, severely suppressed bone turnover.

Received December 20, 2007.

Accepted May 22, 2008.


   References
Top
 Abstract
 Introduction
 Case 1
 Case 2
 Case 3
 Discussion
 References
 

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