An Evaluative History of Bisphosphonate Drugs: Dual Physiologic Effects of Pyrophosphate as Inspiration for a Novel Pharmaceutical Class

Hinshaw, William B.; DeLong, Allyn F.

doi:10.1155/2016/1426279

Cited by 4 publications

(3 citation statements)

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“…HPP produces [48] elevated levels of pyrophosphate (PPi) secondary to low levels of alkaline phosphatase. Despite opinions to the contrary [24], the dual biological activity of PPi has been shown to be similar the BPs [49,50,51]. Like the bisphosphonates illustrated in this paper, PPi has both antiresorptive (cellular) and mineralization inhibitory activity.…”

Section: Metatarsalmentioning

confidence: 69%

“…Another hereditary syndrome, adult hypophosphatasia [95,52], includes failure of adequate alkaline phosphatase synthesis, causing high blood levels of pyrophosphate. The physiologic action of pyrophosphate was the model for the discovery of the BP antiresorptive activity activity [96,51]. AFF-like femur fractures, metatarsal fractures, and alveolar bone dysfunction are observed in adult hypophosphatasia.…”

Section: Causality Of Bisphosphonate-related Fracturesmentioning

confidence: 99%

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Bisphosphonate-associated Atypical Fractures that are not “Atypical Femoral Fractures”

Hinshaw¹,

Schneider²

2017

BJMMR

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Section: Metatarsalmentioning

confidence: 69%

Section: Causality Of Bisphosphonate-related Fracturesmentioning

confidence: 99%

Bisphosphonate-associated Atypical Fractures that are not “Atypical Femoral Fractures”

Hinshaw¹,

Schneider²

2017

BJMMR

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“…The example he gave was rather weak. But there have been some striking analogies to the drug-induced osteonecrosis and atypical femur fractures pointed out once an understanding developed that effects of bisphosphonates paralleled those of the analogous pyrophosphoric acid [47]. The discovery of the antiresorptive effects of the drugs was preceded by discovery of the antiresorptive effects of pyrophosphoric acid in physiologic conditions in three laboratories in the interval 1968-1980 [48][49][50].…”

Section: Establishing a Meaningful Definition Of Causationmentioning

confidence: 99%

The Causation of “Bisphosphonate-Associated” Atypical Femur Fractures

Hinshaw¹

2020

BJSTR

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The last decades of the 20 th century saw the development of intense research programs directed toward the reduction of low-trauma fracture risk by the use of preventative medications. It is not the intention here to recite the history of these efforts, as these have been amply described elsewhere. After the turn of the century, it became apparent that the introduction of the bisphosphonate medications for the purpose was associated with a number of unfortunate consequences. Among these number the appearance of unanticipated necrosis of the mandible and/or maxilla and similarly unanticipated (or almost unanticipated) spontaneous fractures of the subtrochanteric femur. There followed a vigorous response by the medical community to these cataclysmic events. This response was exemplified by the convening, after a number of years of case-reports multiplying in the literature, by the American Society of Bone and Mineral Research, of select groups of concerned physicians and scientists tasked with evaluating the origins of these problems.At no time did these so-called Task Forces acknowledge clearly and unambiguously that the preponderance of evidence was consistent with the cause of these dramatic effects being the associated use of the bisphosphonate drugs. The purpose of this opinion paper is to show that the problem of assigning causation, a conundrum which has resulted in contrary opinions of many eminent philosophers, has indeed been convincingly elucidated in a manner that has received acceptance and recognition in the field of applied medicine, and furthermore, to show the application of this technique to the question of the causation of the effects "associated" with the bisphosphonates, with particular reference to the femur fractures mentioned above.

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