- Email: [email protected]
Moderate osteoporosis itself is beneficial for bones
Medical Hypotheses 134 (2020) 109427
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Moderate osteoporosis itself is beneficial for bones a
a
a
Zhonghua Xiong , Jiayu Wu , Zhenjun Liu , Wei Jing
b,⁎
T
a
Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science & Technology of China, Chengdu, PR China State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China b
A B S T R A C T
There have been increasing numbers of reports that anti-osteoporosis drugs cause osteonecrosis. A typical example is medication-related osteonecrosis of the jaws (MRONJ) which can cause massive necrosis and defects of the jaws. Thus, the dosage and effects of anti-osteoporosis drugs should be re-examined. Our hypothesis is that primary moderate osteoporosis itself is beneficial for bones and should not be excessively treated other than vitamin D, calcium supplementation and functional exercises. The self-repair and anti-infection abilities of bone depend on its organic tissues including stem cells, blood vessels, osteoclastic and osteogenic factors in bone, which jointly fight against invading pathogens and repair bone damage. Recent evidence supports age-related changes in mesenchymal stem cell including loss of self-renewal and increases in senescent cell numbers. Thus, the number of MSCs and vessels need to be increased to achieve functions similar to those in young people. This requires dissolving a portion of inorganic materials and providing extra space to hold more cells and blood vessels. In contrast, anti-osteoporosis drugs prevent bone destruction, and increase mineralization that occupies the space of organic materials, reduces bone immunity and self-repair. Moreover, long term use of anti-osteoporosis drugs also have negative effects on long bones and cartilages. Therefore, moderate age-related osteoporosis is natural in humans to protect bones. Excessive treatment of osteoporosis weakens immunity and self-repair.
Introduction Over the last few years, there have been increasing numbers of reports that anti-osteoporosis drugs cause osteonecrosis [1], which has a drastic effect on patient health and is particularly refractory. Thus, the dosage and side effects of anti-osteoporosis drugs should be re-examined. Primary osteoporosis is a normal physiological process and an inevitable condition of aging [2]. While active treatment of secondary osteoporosis is justified, excessive use of drugs to reverse natural and slow onset senile primary osteoporosis should be avoided because excessive intervention will increase the risk of osteonecrosis. Alternatively, other measures including calcium and vitamin D supplementation and functional exercise can be applied to prevent fractures.
senescent cell numbers [3]. Thus, the number of MSCs needs to be increased to achieve functions similar to those in young people. This phenomenon has been observed in aged rats following orthopedic surgery, in which the number of MSCs was adaptively increased to compensate for the lack of cellular functions [4]. This requires dissolving a portion of inorganic materials and providing extra space to hold more cells and blood vessels. Therefore, at the expense of moderate osteoporosis, the improvements in bone immunity and self-repair facilitate maintaining bone homeostasis and health. In contrast, anti-osteoporosis drugs prevent bone destruction, and increase mineralization that occupies the space of organic materials, reduces bone immunity and self-repair which makes patients more prone to infection and necrosis.
The hypothesis
Evaluation of the hypothesis
Our hypothesis is that moderate osteoporosis itself is beneficial for bones, which can be considered in terms of stem cells and vascular aging. The self-repair and anti-infection abilities of bone depend on its organic tissues. The stem cells, blood vessels, antibodies, osteoclastic and osteogenic factors in bone jointly fight against invading pathogens and repair bone damage. Recent evidence supports age-related changes in mesenchymal stem cell including loss of self-renewal and increases in
A typical example is medication-related osteonecrosis of the jaws (MRONJ), a drug-induced serious complication of anti-osteoporosis therapy or therapy to prevent bone metastasis [5,6], which can cause massive necrosis and defects of the jaws, leading to facial deformities and dysfunction. The risk of MRONJ differs among studies and is up to about 10% in some reports [7–9]. While tooth extraction increases the risk of osteonecrosis of the jaws [9], bone deterioration after drug use
⁎ Corresponding author at: No. 14, 3rd sec, Ren Min Nan Road, Department of Oral Maxillofacial Surgery, West China College of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China. E-mail address: [email protected] (W. Jing).
https://doi.org/10.1016/j.mehy.2019.109427 Received 21 August 2019; Received in revised form 30 September 2019; Accepted 9 October 2019 0306-9877/ © 2019 Published by Elsevier Ltd.
Medical Hypotheses 134 (2020) 109427
Z. Xiong, et al.
osteonecrosis or increased fragility. Moreover, attention should be paid to the jaws, because this area has a rich blood supply that can lead to unexpected drug reactions, along with cosmetic considerations. Nevertheless, active prevention and treatment are still necessary for secondary osteoporosis.
remains as the main cause. The reason why osteonecrosis occurs only in jaws and rarely in limbs is unclear. A possible explanation may be that the blood supply of jaw bones is more abundant than that of limb bones, which leads to higher accumulated drug toxicity in the jaws. As a result, excessive mineralization of the jaws severely narrows the space available for blood vessels and decreases the immunity of jaws, which makes patients more prone to infection and necrosis. This is similar to the mechanism of osteoradionecrosis of the jaws. However, MRONJ occurs almost exclusively in elderly patients, suggesting that moderate osteoporosis may occur in the jaws of elderly patients without excessive mineralization. Moreover, jaw bone necrosis is induced by not only bisphosphonates, but also anti-RANKL antibodies, molecular targeted agents, and steroids [10]. Hyperbaric oxygen therapy will be beneficial in the treatment of MRONJ. Similarly, excessive use of anti-osteoporosis drugs also has adverse effects on long bones. Notably, long term use of bisphosphonates increases the risk of femoral fractures [11], because excessive bone mineralization reduces bone bending strength and increases fragility. Moreover, the influence of these drugs on the healing rate of fractures is controversial. Some studies suggest that bisphosphonates slow fracture healing [12], because these drugs not only affect osteoclastogenesis, but also have significant effects on osteogenesis. In addition, the reduction in stem cells and blood vessels leads to a decrease in the bone self-repair ability. It has also been reported that the use of bisphosphonates causes wrist scaphoid osteomyelitis [13]. Therefore, a certain degree of osteoporosis should be maintained in elderly individuals to improve bone bending strength and self-repair. Another example is dental implants. These implants can be well installed in normal jaws and coexist for decades. However, such coexistence is broken after the use of bisphosphonates, and the implants become poorly bound to both soft and hard tissues [14]. Anti-osteoporosis drugs can also affect cartilage. Alarmingly, they can cause calcification of intervertebral discs, leading to degenerative disc disease, because excessive calcification hinders the entry of nutrients and oxygen into the deep parts of the cartilage [15]. Cartilage in other sites can also be affected [16].
Conflicts of interest statement The authors have no conflicts of interest to declare. Funding This work was supported by the Natural Science Foundation of China (NSFC) (81971319, 81571366). References [1] Katsarelis H, Shah NP, Dhariwal DK, Pazianas M. Infection and medication-related osteonecrosis of the jaw. J Dent Res 2015 Apr;94(4):534–9. [2] Chen LR, Ko NY, Chen KH. Medical treatment for osteoporosis: from molecular to clinical opinions. Int J Mol Sci 2019;20(9). [3] Chen X, Wang L, Hou J, et al. Study on the dynamic biological characteristics of human bone marrow mesenchymal stem cell senescence. Stem Cells Int 2019;4(2019):9271595. https://doi.org/10.1155/2019/9271595. [4] Piet J, Hu D, Meslier Q, et al. Increased cellular presence after sciatic neurectomy improves the bone mechano-adaptive response in aged mice. Calcif Tissue Int 2019;105(3):316–30. [5] Shin WJ, Kim CH. Prognostic factors for outcome of surgical treatment in medication-related osteonecrosis of the jaw. J Korean Assoc Oral Maxillofac Surg 2018;44(4):174–81. [6] Goller-Bulut D, Özcan G, Avci F. Changes in dimension of neurovascular canals in the mandible and maxilla: A radiographic finding in patients diagnosed with MRONJ. Med Oral Patol Oral Cir Bucal 2018;23(3):e282–9. [7] American Dental Association Council on Scientific Affairs. Dental management of patients receiving oralbisphosphonate therapy: expert panel recommendations. J Am Dent Assoc 2006;137(8):1144–50. [8] Günaldi M, Afsar CU, Duman BB, et al. Effect of the cumulative dose of zoledronic acid on the pathogenesis of osteonecrosis of the jaws. Oncol Lett 2015;10(1):439–42. [9] Kos M. Incidence and risk predictors for osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. Arch Med Sci 2015;11(2):319–24. [10] Egloff-Juras C, Gallois A, Salleron J, et al. Denosumab-related osteonecrosis of the jaw: A retrospective study. J Oral Pathol Med 2018;47(1):66–70. [11] Lloyd AA, Gludovatz B, Riedel C, et al. Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance. Proc Natl Acad Sci USA 2017;114(33):8722–7. [12] Begkas D, Pastroudis A, Touzopoulos P, et al. The effects of long-term use of nitrogen-containing bisphosphonates on fracture healing. Cureus 2019;11(3):e4307. [13] Sun ZW, Li ZY, Yu D, et al. Bisphosphonate-related osteonecrosis of the jaw complicated with wrist scaphoid osteomyelitis: a case report. Hua Xi Kou Qiang Yi Xue Za Zhi 2019;37(2):224–8. [14] Touyz LZG, Afrashtehfar KI. Implications of bisphosphonate calcium ion depletion interfering with desmosome epithelial seal in osseointegrated implants and pressure ulcers. Med Hypotheses 2017;107:22–5. [15] Sun Z, Luo ZJ. Osteoporosis therapies might lead to intervertebral disc degeneration via affecting cartilage endplate. Med Hypotheses 2019;125:5–7. [16] Haj-Mirzaian A, Guermazi A, Roemer FW, et al. Bisphosphonates intake and its association with changes of periarticular bone area and three-dimensional shape: data from the Osteoarthritis Initiative (OAI). Osteoarthritis Cartilage 2018;26(4):564–8.
Consequences of the hypothesis and discussion Therefore, primary and moderate osteoporosis is natural in humans to protect bones. At the cost of dissolving some inorganic tissues, bones accommodate more organic tissues such as blood vessels and cells to compensate for the decreased immunity and self-repair associated with aging. This could be determined by animal studies of osteoporosis rat models, in which the bone density, vessel density, and cell numbers can be measured and compared before and after bisphosphonate treatment. Excessive treatment of osteoporosis weakens immunity and self-repair. For elderly individuals with osteoporosis, calcium and vitamin D supplementation can be adopted, while attention should be paid to avoiding trauma and preventing fractures. If anti-osteoporosis drugs are required, a low dose can be considered to avoid secondary
2
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Moderate osteoporosis itself is beneficial for bones a
a
a
Zhonghua Xiong , Jiayu Wu , Zhenjun Liu , Wei Jing
b,⁎
T
a
Sichuan Cancer Hospital & Institute, School of Medicine, University of Electronic Science & Technology of China, Chengdu, PR China State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China b
A B S T R A C T
There have been increasing numbers of reports that anti-osteoporosis drugs cause osteonecrosis. A typical example is medication-related osteonecrosis of the jaws (MRONJ) which can cause massive necrosis and defects of the jaws. Thus, the dosage and effects of anti-osteoporosis drugs should be re-examined. Our hypothesis is that primary moderate osteoporosis itself is beneficial for bones and should not be excessively treated other than vitamin D, calcium supplementation and functional exercises. The self-repair and anti-infection abilities of bone depend on its organic tissues including stem cells, blood vessels, osteoclastic and osteogenic factors in bone, which jointly fight against invading pathogens and repair bone damage. Recent evidence supports age-related changes in mesenchymal stem cell including loss of self-renewal and increases in senescent cell numbers. Thus, the number of MSCs and vessels need to be increased to achieve functions similar to those in young people. This requires dissolving a portion of inorganic materials and providing extra space to hold more cells and blood vessels. In contrast, anti-osteoporosis drugs prevent bone destruction, and increase mineralization that occupies the space of organic materials, reduces bone immunity and self-repair. Moreover, long term use of anti-osteoporosis drugs also have negative effects on long bones and cartilages. Therefore, moderate age-related osteoporosis is natural in humans to protect bones. Excessive treatment of osteoporosis weakens immunity and self-repair.
Introduction Over the last few years, there have been increasing numbers of reports that anti-osteoporosis drugs cause osteonecrosis [1], which has a drastic effect on patient health and is particularly refractory. Thus, the dosage and side effects of anti-osteoporosis drugs should be re-examined. Primary osteoporosis is a normal physiological process and an inevitable condition of aging [2]. While active treatment of secondary osteoporosis is justified, excessive use of drugs to reverse natural and slow onset senile primary osteoporosis should be avoided because excessive intervention will increase the risk of osteonecrosis. Alternatively, other measures including calcium and vitamin D supplementation and functional exercise can be applied to prevent fractures.
senescent cell numbers [3]. Thus, the number of MSCs needs to be increased to achieve functions similar to those in young people. This phenomenon has been observed in aged rats following orthopedic surgery, in which the number of MSCs was adaptively increased to compensate for the lack of cellular functions [4]. This requires dissolving a portion of inorganic materials and providing extra space to hold more cells and blood vessels. Therefore, at the expense of moderate osteoporosis, the improvements in bone immunity and self-repair facilitate maintaining bone homeostasis and health. In contrast, anti-osteoporosis drugs prevent bone destruction, and increase mineralization that occupies the space of organic materials, reduces bone immunity and self-repair which makes patients more prone to infection and necrosis.
The hypothesis
Evaluation of the hypothesis
Our hypothesis is that moderate osteoporosis itself is beneficial for bones, which can be considered in terms of stem cells and vascular aging. The self-repair and anti-infection abilities of bone depend on its organic tissues. The stem cells, blood vessels, antibodies, osteoclastic and osteogenic factors in bone jointly fight against invading pathogens and repair bone damage. Recent evidence supports age-related changes in mesenchymal stem cell including loss of self-renewal and increases in
A typical example is medication-related osteonecrosis of the jaws (MRONJ), a drug-induced serious complication of anti-osteoporosis therapy or therapy to prevent bone metastasis [5,6], which can cause massive necrosis and defects of the jaws, leading to facial deformities and dysfunction. The risk of MRONJ differs among studies and is up to about 10% in some reports [7–9]. While tooth extraction increases the risk of osteonecrosis of the jaws [9], bone deterioration after drug use
⁎ Corresponding author at: No. 14, 3rd sec, Ren Min Nan Road, Department of Oral Maxillofacial Surgery, West China College of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China. E-mail address: [email protected] (W. Jing).
https://doi.org/10.1016/j.mehy.2019.109427 Received 21 August 2019; Received in revised form 30 September 2019; Accepted 9 October 2019 0306-9877/ © 2019 Published by Elsevier Ltd.
Medical Hypotheses 134 (2020) 109427
Z. Xiong, et al.
osteonecrosis or increased fragility. Moreover, attention should be paid to the jaws, because this area has a rich blood supply that can lead to unexpected drug reactions, along with cosmetic considerations. Nevertheless, active prevention and treatment are still necessary for secondary osteoporosis.
remains as the main cause. The reason why osteonecrosis occurs only in jaws and rarely in limbs is unclear. A possible explanation may be that the blood supply of jaw bones is more abundant than that of limb bones, which leads to higher accumulated drug toxicity in the jaws. As a result, excessive mineralization of the jaws severely narrows the space available for blood vessels and decreases the immunity of jaws, which makes patients more prone to infection and necrosis. This is similar to the mechanism of osteoradionecrosis of the jaws. However, MRONJ occurs almost exclusively in elderly patients, suggesting that moderate osteoporosis may occur in the jaws of elderly patients without excessive mineralization. Moreover, jaw bone necrosis is induced by not only bisphosphonates, but also anti-RANKL antibodies, molecular targeted agents, and steroids [10]. Hyperbaric oxygen therapy will be beneficial in the treatment of MRONJ. Similarly, excessive use of anti-osteoporosis drugs also has adverse effects on long bones. Notably, long term use of bisphosphonates increases the risk of femoral fractures [11], because excessive bone mineralization reduces bone bending strength and increases fragility. Moreover, the influence of these drugs on the healing rate of fractures is controversial. Some studies suggest that bisphosphonates slow fracture healing [12], because these drugs not only affect osteoclastogenesis, but also have significant effects on osteogenesis. In addition, the reduction in stem cells and blood vessels leads to a decrease in the bone self-repair ability. It has also been reported that the use of bisphosphonates causes wrist scaphoid osteomyelitis [13]. Therefore, a certain degree of osteoporosis should be maintained in elderly individuals to improve bone bending strength and self-repair. Another example is dental implants. These implants can be well installed in normal jaws and coexist for decades. However, such coexistence is broken after the use of bisphosphonates, and the implants become poorly bound to both soft and hard tissues [14]. Anti-osteoporosis drugs can also affect cartilage. Alarmingly, they can cause calcification of intervertebral discs, leading to degenerative disc disease, because excessive calcification hinders the entry of nutrients and oxygen into the deep parts of the cartilage [15]. Cartilage in other sites can also be affected [16].
Conflicts of interest statement The authors have no conflicts of interest to declare. Funding This work was supported by the Natural Science Foundation of China (NSFC) (81971319, 81571366). References [1] Katsarelis H, Shah NP, Dhariwal DK, Pazianas M. Infection and medication-related osteonecrosis of the jaw. J Dent Res 2015 Apr;94(4):534–9. [2] Chen LR, Ko NY, Chen KH. Medical treatment for osteoporosis: from molecular to clinical opinions. Int J Mol Sci 2019;20(9). [3] Chen X, Wang L, Hou J, et al. Study on the dynamic biological characteristics of human bone marrow mesenchymal stem cell senescence. Stem Cells Int 2019;4(2019):9271595. https://doi.org/10.1155/2019/9271595. [4] Piet J, Hu D, Meslier Q, et al. Increased cellular presence after sciatic neurectomy improves the bone mechano-adaptive response in aged mice. Calcif Tissue Int 2019;105(3):316–30. [5] Shin WJ, Kim CH. Prognostic factors for outcome of surgical treatment in medication-related osteonecrosis of the jaw. J Korean Assoc Oral Maxillofac Surg 2018;44(4):174–81. [6] Goller-Bulut D, Özcan G, Avci F. Changes in dimension of neurovascular canals in the mandible and maxilla: A radiographic finding in patients diagnosed with MRONJ. Med Oral Patol Oral Cir Bucal 2018;23(3):e282–9. [7] American Dental Association Council on Scientific Affairs. Dental management of patients receiving oralbisphosphonate therapy: expert panel recommendations. J Am Dent Assoc 2006;137(8):1144–50. [8] Günaldi M, Afsar CU, Duman BB, et al. Effect of the cumulative dose of zoledronic acid on the pathogenesis of osteonecrosis of the jaws. Oncol Lett 2015;10(1):439–42. [9] Kos M. Incidence and risk predictors for osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. Arch Med Sci 2015;11(2):319–24. [10] Egloff-Juras C, Gallois A, Salleron J, et al. Denosumab-related osteonecrosis of the jaw: A retrospective study. J Oral Pathol Med 2018;47(1):66–70. [11] Lloyd AA, Gludovatz B, Riedel C, et al. Atypical fracture with long-term bisphosphonate therapy is associated with altered cortical composition and reduced fracture resistance. Proc Natl Acad Sci USA 2017;114(33):8722–7. [12] Begkas D, Pastroudis A, Touzopoulos P, et al. The effects of long-term use of nitrogen-containing bisphosphonates on fracture healing. Cureus 2019;11(3):e4307. [13] Sun ZW, Li ZY, Yu D, et al. Bisphosphonate-related osteonecrosis of the jaw complicated with wrist scaphoid osteomyelitis: a case report. Hua Xi Kou Qiang Yi Xue Za Zhi 2019;37(2):224–8. [14] Touyz LZG, Afrashtehfar KI. Implications of bisphosphonate calcium ion depletion interfering with desmosome epithelial seal in osseointegrated implants and pressure ulcers. Med Hypotheses 2017;107:22–5. [15] Sun Z, Luo ZJ. Osteoporosis therapies might lead to intervertebral disc degeneration via affecting cartilage endplate. Med Hypotheses 2019;125:5–7. [16] Haj-Mirzaian A, Guermazi A, Roemer FW, et al. Bisphosphonates intake and its association with changes of periarticular bone area and three-dimensional shape: data from the Osteoarthritis Initiative (OAI). Osteoarthritis Cartilage 2018;26(4):564–8.
Consequences of the hypothesis and discussion Therefore, primary and moderate osteoporosis is natural in humans to protect bones. At the cost of dissolving some inorganic tissues, bones accommodate more organic tissues such as blood vessels and cells to compensate for the decreased immunity and self-repair associated with aging. This could be determined by animal studies of osteoporosis rat models, in which the bone density, vessel density, and cell numbers can be measured and compared before and after bisphosphonate treatment. Excessive treatment of osteoporosis weakens immunity and self-repair. For elderly individuals with osteoporosis, calcium and vitamin D supplementation can be adopted, while attention should be paid to avoiding trauma and preventing fractures. If anti-osteoporosis drugs are required, a low dose can be considered to avoid secondary
2