Aging and bone loss: new insights for the clinician

It is well known that the underlying mechanisms of osteoporosis in older adults are different than those associated with estrogen deprivation. Age-related bone loss involves a gradual and progressive decline, which is also seen in men. Markedly increased bone resorption leads to the initial fall in bone mineral density. With increasing age, there is also a significant reduction in bone formation. This is mostly due to a shift from osteoblastogenesis to predominant adipogenesis in the bone marrow, which also has a lipotoxic effect that affects matrix formation and mineralization. We review new evidence on the pathophysiology of age-related bone loss with emphasis upon the mechanism of action of current osteoporosis treatments. New potential treatments are also considered, including therapeutic approaches to osteoporosis in the elderly that focus on the pathophysiology and potential reversal of adipogenic shift in bone.

[1]  S. Khosla,et al.  Bone turnover across the menopause transition: correlations with inhibins and follicle-stimulating hormone. , 2006, The Journal of clinical endocrinology and metabolism.

[2]  G. Duque,et al.  Alendronate Has an Anabolic Effect on Bone Through the Differentiation of Mesenchymal Stem Cells , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[3]  G. Duque,et al.  Age-related changes in lamin A/C expression in the osteoarticular system: Laminopathies as a potential new aging mechanism , 2006, Mechanisms of Ageing and Development.

[4]  B. Riggs,et al.  Pathophysiology of age-related bone loss and osteoporosis. , 2005, Endocrinology and metabolism clinics of North America.

[5]  P. Lips Vitamin D status and nutrition in Europe and Asia , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[6]  L. Mosekilde,et al.  Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis , 2004, Biogerontology.

[7]  S. Mohan,et al.  Concentrations of insulin-like growth factor (IGF)-I, -II, and IGF binding protein-4, and -5 in human bone cell conditioned medium do not change with age , 2000, Mechanisms of Ageing and Development.

[8]  B. Riggs,et al.  The role of the immune system in the pathophysiology of osteoporosis , 2005, Immunological reviews.

[9]  J. Caverzasio Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms. , 2008, Bone.

[10]  D. Schoenfeld,et al.  Differential effects of androgens and estrogens on bone turnover in normal men. , 2003, The Journal of clinical endocrinology and metabolism.

[11]  L. Melton,et al.  Involutional osteoporosis. , 1986, The New England journal of medicine.

[12]  Pierre Cau,et al.  Lamin A Truncation in Hutchinson-Gilford Progeria , 2003, Science.

[13]  O. MacDougald,et al.  Regulation of bone mass by Wnt signaling. , 2006, The Journal of clinical investigation.

[14]  B. Clarke Older Men With Low Serum Estradiol and High Serum SHBG Have an Increased Risk of Fractures , 2009 .

[15]  M. Jensen,et al.  Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. , 1999, Endocrinology.

[16]  L. Duong,et al.  Effect of the Cathepsin K Inhibitor Odanacatib on Bone Resorption Biomarkers in Healthy Postmenopausal Women: Two Double‐Blind, Randomized, Placebo‐Controlled Phase I Studies , 2009, Clinical pharmacology and therapeutics.

[17]  Dennis E. Discher,et al.  Physical plasticity of the nucleus in stem cell differentiation , 2007, Proceedings of the National Academy of Sciences.

[18]  R. Baron,et al.  In vitro effects of S12911-2 on osteoclast function and bone marrow macrophage differentiation. , 2002, European journal of pharmacology.

[19]  L. McCabe,et al.  Inhibition of PPARγ prevents type I diabetic bone marrow adiposity but not bone loss , 2006, Journal of cellular physiology.

[20]  A. Economides,et al.  0163-769X/03/$20.00/0 Endocrine Reviews 24(2):218–235 Printed in U.S.A. Copyright © 2003 by The Endocrine Society doi: 10.1210/er.2002-0023 Bone Morphogenetic Proteins, Their Antagonists, and the Skeleton , 2022 .

[21]  C. Slemenda,et al.  Sex steroids, bone mass, and bone loss. A prospective study of pre-, peri-, and postmenopausal women. , 1996, The Journal of clinical investigation.

[22]  L. Suva,et al.  Aging alters the skeletal response to disuse in the rat. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.

[23]  Wei Li,et al.  Age-related bone loss in the LOU/c rat model of healthy ageing , 2009, Experimental Gerontology.

[24]  P Geusens,et al.  Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. , 2001, The New England journal of medicine.

[25]  M. Macoritto,et al.  Interferon‐γ plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[26]  S. Boonen,et al.  Zoledronic acid and clinical fractures and mortality after hip fracture. , 2007, The New England journal of medicine.

[27]  J. Bilezikian,et al.  Glucocorticoid-induced osteoporosis: pathophysiology and therapy , 2007, Osteoporosis International.

[28]  M. Kneissel The promise of sclerostin inhibition for the treatment of osteoporosis , 2009 .

[29]  P. Kostenuik,et al.  Targeted Deletion of the Sclerostin Gene in Mice Results in Increased Bone Formation and Bone Strength , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[30]  P. Tugwell,et al.  Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. , 2024, The Cochrane database of systematic reviews.

[31]  Qing Chen,et al.  Sclerostin Antibody Treatment Increases Bone Formation, Bone Mass, and Bone Strength in a Rat Model of Postmenopausal Osteoporosis , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[32]  C. Slemenda,et al.  Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens. , 1997, The Journal of clinical investigation.

[33]  Dami,et al.  EFFECT OF RISEDRONATE ON THE RISK OF HIP FRACTURE IN ELDERLY WOMEN EFFECT OF RISEDRONATE ON THE RISK OF HIP FRACTURE IN ELDERLY WOMEN , 2001 .

[34]  B. L. Riggs,et al.  Effect of Blockade of TNF‐α and Interleukin‐1 Action on Bone Resorption in Early Postmenopausal Women , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[35]  J. Henderson,et al.  Accelerated features of age-related bone loss in zmpste24 metalloproteinase-deficient mice. , 2009, The journals of gerontology. Series A, Biological sciences and medical sciences.

[36]  C. Ackert-Bicknell,et al.  Marrow fat and the bone microenvironment: developmental, functional, and pathological implications. , 2009, Critical reviews in eukaryotic gene expression.

[37]  H K Genant,et al.  Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. , 1999, JAMA.

[38]  D. Fisher,et al.  Pycnodysostosis: role and regulation of cathepsin K in osteoclast function and human disease. , 2002, Current molecular medicine.

[39]  H. Kemper,et al.  The Effect of Exercise Training Programs on Bone Mass: A Meta-analysis of Published Controlled Trials in Pre- and Postmenopausal Women , 1999, Osteoporosis International.

[40]  Kozo Nakamura,et al.  Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts , 2002, The Journal of cell biology.

[41]  R. Lindsay,et al.  Effect of Recombinant Human Parathyroid Hormone (1-84) on Vertebral Fracture and Bone Mineral Density in Postmenopausal Women with Osteoporosis , 2007, Annals of Internal Medicine.

[42]  P. Marie,et al.  The divalent strontium salt S12911 enhances bone cell replication and bone formation in vitro. , 1996, Bone.

[43]  A. Oberg,et al.  Role of parathyroid hormone in mediating age-related changes in bone resorption in men , 2003, Osteoporosis International.

[44]  E. Seeman,et al.  Causes of Age‐Related Bone Loss and Bone Fragility: An Alternative View , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[45]  D. Lacey,et al.  Osteoprotegerin Ligand Is a Cytokine that Regulates Osteoclast Differentiation and Activation , 1998, Cell.

[46]  S. Cummings,et al.  Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures , 1996, The Lancet.

[47]  J. Dungan Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis , 2010 .

[48]  D. Lacey,et al.  Estrogen stimulates gene expression and protein production of osteoprotegerin in human osteoblastic cells. , 1999, Endocrinology.

[49]  R. Rizzoli,et al.  Odanacatib in the treatment of postmenopausal women with low bone mineral density: Three‐year continued therapy and resolution of effect , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[50]  P. Delmas,et al.  Influence of mature adipocytes on osteoblast proliferation in human primary cocultures. , 2000, Bone.

[51]  J. Gimble,et al.  Playing with bone and fat , 2006, Journal of cellular biochemistry.

[52]  P Meunier,et al.  Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. A quantitative study of 84 iliac bone biopsies. , 1971, Clinical orthopaedics and related research.

[53]  D. Fatkin,et al.  Attenuated anabolic response to exercise in lamin A/C haploinsufficient mice. , 2011, Bone.

[54]  D. Brömme,et al.  The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. , 2005, Advanced drug delivery reviews.

[55]  P. Tugwell,et al.  Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. , 2008, The Cochrane database of systematic reviews.

[56]  A Simkin,et al.  Gain in mass density of bone following strenuous physical activity , 1989, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[57]  E. Seeman From Density to Structure: Growing Up and Growing Old on the Surfaces of Bone , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[58]  B. Riggs,et al.  Relation of Serum Serotonin Levels to Bone Density and Structural Parameters in Women , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[59]  B. Clarke,et al.  Effect of Recombinant Human Parathyroid Hormone (1-84) on Vertebral Fracture and Bone Mineral Density in Postmenopausal Women with Osteoporosis: A Randomized Trial , 2008 .

[60]  Sundeep Khosla,et al.  Population‐Based Study of Age and Sex Differences in Bone Volumetric Density, Size, Geometry, and Structure at Different Skeletal Sites , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[61]  D. Felson,et al.  Osteoporosis in Men , 2001, Journal of the Royal Society of Medicine.

[62]  S. Goldstein,et al.  Transgenic Models of Metabolic Bone Disease: Impact of Estrogen Receptor Deficiency on Skeletal Metabolism , 2003, Connective tissue research.

[63]  K. Smans,et al.  Neuro-hormonal control of bone metabolism: vasoactive intestinal peptide stimulates alkaline phosphatase activity and mRNA expression in mouse calvarial osteoblasts as well as calcium accumulation mineralized bone nodules , 1999, Regulatory Peptides.

[64]  B. Troen,et al.  Understanding the Mechanisms of Senile Osteoporosis: New Facts for a Major Geriatric Syndrome , 2008, Journal of the American Geriatrics Society.

[65]  Giselle Chamberlain,et al.  Concise Review: Mesenchymal Stem Cells: Their Phenotype, Differentiation Capacity, Immunological Features, and Potential for Homing , 2007, Stem cells.

[66]  J. Reginster,et al.  Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. , 2001, The New England journal of medicine.

[67]  A. Grey Skeletal consequences of thiazolidinedione therapy , 2008, Osteoporosis International.

[68]  G. Duque As a matter of fat: New perspectives on the understanding of age-related bone loss , 2007 .

[69]  L. Donahue,et al.  Insulin-like Growth Factors and Bone: The Osteoporosis Connection , 1994, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[70]  P. Lips,et al.  Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. , 2001, Endocrine reviews.

[71]  Sundeep Khosla,et al.  Sex steroids and the construction and conservation of the adult skeleton. , 2002, Endocrine reviews.

[72]  Ego Seeman,et al.  Pathogenesis of bone fragility in women and men , 2002, The Lancet.

[73]  J. Launay,et al.  In vitro production of cytokines by bone surface-derived osteoblastic cells in normal and osteoporotic postmenopausal women: relationship with cell proliferation. , 1993, The Journal of clinical endocrinology and metabolism.

[74]  R. Considine,et al.  Serum immunoreactive-leptin concentrations in normal-weight and obese humans. , 1996, The New England journal of medicine.

[75]  S. Boonen,et al.  Zoledronic Acid in Reducing Clinical Fracture and Mortality after Hip Fracture. , 2007, The New England journal of medicine.

[76]  D. Lacey,et al.  Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. , 2003, The Journal of clinical investigation.

[77]  J. Reginster,et al.  Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. , 2005, The Journal of clinical endocrinology and metabolism.

[78]  J. Reginster,et al.  Long-term treatment of postmenopausal osteoporosis with strontium ranelate: results at 8 years. , 2009, Bone.

[79]  Chao Wan,et al.  Oxygen Sensing and Osteogenesis , 2007, Annals of the New York Academy of Sciences.

[80]  M. Burritt,et al.  Role of parathyroid hormone in mediating nocturnal and age-related increases in bone resorption. , 1995, The Journal of clinical endocrinology and metabolism.

[81]  K. Lindpaintner,et al.  Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease , 2002, Journal of medical genetics.

[82]  C. Becker Another selective estrogen-receptor modulator for osteoporosis. , 2010, The New England journal of medicine.

[83]  L. Melton,et al.  High Serum IGFBP‐2 Is Predictive of Increased Bone Turnover in Aging Men and Women , 2007, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[84]  L. Melton,et al.  Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. , 2001, The Journal of clinical endocrinology and metabolism.

[85]  D. Lacey,et al.  Osteoprotegerin and osteoprotegerin ligand effects on osteoclast formation from human peripheral blood mononuclear cell precursors , 1999, Journal of cellular biochemistry.

[86]  T. Spector,et al.  Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies , 2004, The New England journal of medicine.

[87]  S. Berney,et al.  Once-Yearly Zoledronic Acid for Treatment of Postmenopausal Osteoporosis , 2008 .

[88]  Patricia Ducy,et al.  Leptin Regulates Bone Formation via the Sympathetic Nervous System , 2002, Cell.

[89]  M. Rybchyn,et al.  Osteoblasts play key roles in the mechanisms of action of strontium ranelate , 2009, British journal of pharmacology.

[90]  J Reeve,et al.  Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. , 1980, British medical journal.

[91]  J. Kaufman,et al.  Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and discontinuation of therapy , 2005, Osteoporosis International.

[92]  Arndt F Schilling,et al.  Leptin Inhibits Bone Formation through a Hypothalamic Relay A Central Control of Bone Mass , 2000, Cell.

[93]  Ping Chung Leung,et al.  Vertebral bone mineral density, marrow perfusion, and fat content in healthy men and men with osteoporosis: dynamic contrast-enhanced MR imaging and MR spectroscopy. , 2005, Radiology.

[94]  M. Kumegawa,et al.  Direct stimulation of osteoclastic bone resorption by bone morphogenetic protein (BMP)-2 and expression of BMP receptors in mature osteoclasts. , 2000, Bone.

[95]  M. Hiligsmann,et al.  Strontium ranelate: long-term efficacy against vertebral, nonvertebral and hip fractures in patients with postmenopausal osteoporosis , 2010, Therapeutic advances in musculoskeletal disease.

[96]  Joel S Greenberger,et al.  Age‐related intrinsic changes in human bone‐marrow‐derived mesenchymal stem cells and their differentiation to osteoblasts , 2008, Aging cell.

[97]  J. Reginster,et al.  Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial , 2009, The Lancet.

[98]  P. Lehenkari,et al.  Vasoactive Intestinal Peptide (VIP)/Pituitary Adenylate Cyclase-Activating Peptide Receptor Subtypes in Mouse Calvarial Osteoblasts: Presence of VIP-2 Receptors and Differentiation-Induced Expression of VIP-1 Receptors * * The present study was supported by grants from the Swedish Medical Research C , 2001, Endocrinology.

[99]  C. Christiansen,et al.  Effects of Oral Ibandronate Administered Daily or Intermittently on Fracture Risk in Postmenopausal Osteoporosis , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[100]  D. Reid,et al.  Efficacy and Safety of Daily Risedronate in the Treatment of Corticosteroid‐Induced Osteoporosis in Men and Women: A Randomized Trial , 2000 .

[101]  George P Chrousos,et al.  Positive Linear Growth and Bone Responses to Growth Hormone Treatment in Children With Types III and IV Osteogenesis Imperfecta: High Predictive Value of the Carboxyterminal Propeptide of Type I Procollagen , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[102]  S. B. Heymsfield,et al.  MRI-measured bone marrow adipose tissue is inversely related to DXA-measured bone mineral in Caucasian women , 2007, Osteoporosis International.

[103]  H. Worman,et al.  A-type lamins: Guardians of the soma? , 2004, Nature Cell Biology.

[104]  G. Duque,et al.  Severe bone changes in a case of Hutchinson-Gilford syndrome. , 2002, Annales de genetique.

[105]  G. Rodan,et al.  Osteopenia in the immobilized rat hind limb is associated with increased bone resorption and decreased bone formation. , 1989, Bone.

[106]  B. Troen The role of cathepsin K in normal bone resorption. , 2004, Drug news & perspectives.

[107]  R. Eastell,et al.  Interrelationship among vitamin D metabolism, true calcium absorption, parathyroid function, and age in women: Evidence of an age‐related intestinal resistance to 1,25‐dihydroxyvitamin D action , 1991, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[108]  W. Vollmer,et al.  Body weight versus body fat distribution, adiposity, and frame size as predictors of bone density. , 1995, The Journal of clinical endocrinology and metabolism.

[109]  G. Mundy,et al.  Estrogen promotes apoptosis of murine osteoclasts mediated by TGF–β , 1996, Nature Medicine.

[110]  J. Eisman,et al.  Volumetric bone density at the femoral neck as a common measure of hip fracture risk for men and women. , 2004, The Journal of clinical endocrinology and metabolism.

[111]  J Denton,et al.  Adipocytic proportion of bone marrow is inversely related to bone formation in osteoporosis , 2002, Journal of clinical pathology.

[112]  S. Friedman,et al.  Parathyroid hormone induces hepatic production of bioactive interleukin-6 and its soluble receptor. , 2001, American journal of physiology. Endocrinology and metabolism.

[113]  S. Silverman,et al.  Anabolic Therapies , 2010, Current osteoporosis reports.

[114]  A. Oberg,et al.  Relationship of volumetric bone density and structural parameters at different skeletal sites to sex steroid levels in women. , 2005, The Journal of clinical endocrinology and metabolism.

[115]  B. Riggs,et al.  Comparison of sex steroid measurements in men by immunoassay versus mass spectroscopy and relationships with cortical and trabecular volumetric bone mineral density , 2008, Osteoporosis International.

[116]  B. Clarke,et al.  Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial , 2009 .

[117]  M. Hooper,et al.  Randomized Trial of the Effects of Risedronate on Vertebral Fractures in Women with Established Postmenopausal Osteoporosis , 2000, Osteoporosis International.

[118]  R. Russell,et al.  Bisphosphonates: from bench to bedside. , 2006, Annals of the New York Academy of Sciences.

[119]  D. Fatkin,et al.  Decreased Bone Formation and Osteopenia in Lamin A/C-Deficient Mice , 2011, PloS one.

[120]  G. Verbeke,et al.  Down‐Regulation of the Serum Stimulatory Components of the Insulin‐like Growth Factor (IGF) System (IGF‐I, IGF‐II, IGF Binding Protein [BP]‐3, and IGFBP‐5) in Age‐Related (Type II) Femoral Neck Osteoporosis , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[121]  X. Guo,et al.  Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo , 2008, Proceedings of the National Academy of Sciences.

[122]  L. Melton,et al.  Relationship between body composition and bone mass in women , 1996, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[123]  R. Lindsay,et al.  Bone mass and body composition in normal women. , 1992, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[124]  E. Posvar,et al.  Single‐dose, placebo‐controlled, randomized study of AMG 785, a sclerostin monoclonal antibody , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[125]  Jacques P. Brown,et al.  Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial. , 2001, Arthritis and rheumatism.

[126]  B. Troen The Regulation of Cathepsin K Gene Expression , 2006, Annals of the New York Academy of Sciences.

[127]  P. Halbout,et al.  Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response , 2009, Osteoporosis International.

[128]  J J Anderson,et al.  Effects of weight and body mass index on bone mineral density in men and women: The framingham study , 1993, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[129]  L. Suva,et al.  Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. , 2007, Endocrinology.

[130]  D. Reid,et al.  Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study. , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[131]  B. Lecka-Czernik PPARs and Bone Metabolism , 2006, PPAR research.

[132]  J. Eisman,et al.  Odanacatib, a cathepsin‐K inhibitor for osteoporosis: A two‐year study in postmenopausal women with low bone density , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[133]  R. Eastell,et al.  Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men. , 2000, The Journal of clinical investigation.

[134]  L. Melton,et al.  Effects of age and estrogen status on serum parathyroid hormone levels and biochemical markers of bone turnover in women: a population-based study. , 1997, The Journal of clinical endocrinology and metabolism.

[135]  E. Orwoll,et al.  Alendronate for the treatment of osteoporosis in men. , 2000, The New England journal of medicine.

[136]  L. Mounkes,et al.  A progeroid syndrome in mice is caused by defects in A-type lamins , 2003, Nature.

[137]  Guoyin Feng,et al.  Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β‐Catenin Signaling , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[138]  N. Takahashi,et al.  S 12911‐2 Inhibits Osteoclastic Bone Resorption In Vitro , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[139]  Y. Wan,et al.  PPAR-γ regulates osteoclastogenesis in mice , 2007, Nature Medicine.

[140]  M Dioszegi,et al.  Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). , 2001, Human molecular genetics.

[141]  W. Rifkin Denosumab in postmenopausal women with low bone mineral density. , 2006, The New England journal of medicine.

[142]  E. Barrett-Connor,et al.  The effects of serum testosterone, estradiol, and sex hormone binding globulin levels on fracture risk in older men. , 2009, The Journal of clinical endocrinology and metabolism.

[143]  P. Delmas,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Bioavailable Estradiol May Be an Important Determinant of Osteoporosis in Men: The MINOS Study* , 2022 .

[144]  B. Riggs,et al.  Human giant cell tumors of the bone (osteoclastomas) are estrogen target cells. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[145]  Kenji F. Tanaka,et al.  A Serotonin-Dependent Mechanism Explains the Leptin Regulation of Bone Mass, Appetite, and Energy Expenditure , 2009, Cell.

[146]  B. Langdahl,et al.  Medical Treatment of Osteoporotic Vertebral Fractures , 2011, Therapeutic advances in musculoskeletal disease.

[147]  S. Khosla Update in male osteoporosis. , 2010, The Journal of clinical endocrinology and metabolism.

[148]  S. Khosla,et al.  Physiology of bone loss. , 2010, Radiologic clinics of North America.

[149]  B. Baggio,et al.  Effects of Unsaturated Free Fatty Acids on Adhesion and on Gene Expression of Extracellular Matrix Macromolecules in Human Osteoblast-like Cell Cultures , 2007, Connective tissue research.

[150]  P. Tugwell,et al.  Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. , 2008, The Cochrane database of systematic reviews.

[151]  P. Lehenkari,et al.  Vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide receptor subtypes in mouse calvarial osteoblasts: presence of VIP-2 receptors and differentiation-induced expression of VIP-1 receptors. , 2001, Endocrinology.

[152]  Mary L Bouxsein,et al.  Mechanisms of Disease: is osteoporosis the obesity of bone? , 2006, Nature Clinical Practice Rheumatology.

[153]  S. Boonen,et al.  Teriparatide or alendronate in glucocorticoid-induced osteoporosis. , 2007, The New England journal of medicine.